Use of pleuromutilins for the treatment of disorders caused by Helicobacter pylori

ABSTRACT

A method of preventing or treating diseases mediated by  Helicobacter pylori , comprising administering to a subject in need of such treatment an effective amount of pleuromutilin.

The present invention relates to Helicobacter pylori treatment, such astreatment of diseases mediated by H.pylori, with pleuromutilins.

Infections with Helicobacter pylori may contribute to diseases such asactive chronic gastritis, peptic ulcer disease and gastricadenocarcinoma, and are also reported to contribute e.g. to malignantlymphoma of mucosa-associated lymphoid tissue of the stomach, chronicrenal failure, HIV, pernicious anemia, Zollinger-Ellison syndrome,choleric polyps. Pharmaceuticals which are currently used in thetreatment of H.pylori infections include antimicrobials, such astetracycline, amoxicillin, metronidazole, clarithromycin, and mixturesof proton-pump inhibitors, such as omeprazole or lansoprazole, togetherwith a second antimicrobial, e.g. amoxicillin or clarithromycin, but amajor problem is the appearance of H. pylori strains which have becomeresistant to one ore several of the above mentioned antibiotics.

We have now surprisingly identified a compound class which showssurprisingly antibacterial activitiy in vitro against H. pylori, andwhich may be useful in the treatment of diseases mediated, e.g. caused,by H. pylori, e.g. even in against drug resistant strains.

In one aspect the present invention provides the use of a pleuromutilinin the preparation of a medicament for the treatment of diseasesmediated by Helicobacter pylori.

In another aspect the present invention provides a method for thetreatment of diseases mediated by Helicobacter pylori, comprisingadministering to a subject in need of such treatment an effective amountof a pleuromutilin.

Diseases mediated by H.pylori or H.pylori infections include e.g. activechronic gastritis, peptic ulcer disease, gastric adenocarcinoma,malignant lymphoma of mucosa-associated lymphoid tissue of the stomach,chronic renal failure, HIV, pernicious anemia, Zollinger-Ellisonsyndrome, choleric polyps, e.g. which diseases are found simultanously.

A pleuromutilin for treatment includes one or more pleuromutilins, e.g.a combination of different pleuromutilins. Treatment includes treatmentand prophylaxis. A pleuromutilin of the present invention includes apleuromutilin in the form of a free base, and, where existing, in theform of a salt, in the form of a solvate and in the form of a salt and asolvate, e.g. and in the form of a complex, such as a cyclodextrincomplex.

A pleuromutilin of the present invention may exist in the form ofisomers and mixtures thereof, e.g. including diastereoisomers andmixtures thereof. Isomeric mixtures may be separated as appropriate,e.g. according to a method as conventional, to obtain pure isomers. Thepresent invention includes a pleuromutilin according to the presentinvention in any isomeric form and in any isomeric mixture, such asdescribed in patent literature cited below, which patent literature isintroduced herein by reference with respect to isomeric forms ofpleuromutlins. Preferably the configuration in the mutilin ring is thesame as in a naturally produced mutilin.

A pleuromutilin for use according to the present invention or fortreating diseases according to the present invention is designatedhereinafter as “a pleuromutilin(s) of (according to) the presentinvention”.

Pleuromutilin, a compound of formula

is a naturally occurring antibiotic, e.g. produced by the basidomycetesPleurotus mutilus and P.passeckerianus, see e.g. The Merck Index, 12thedition, item 7694.

A number of further pleuromutilins having the principle ring structureof pleuromutilin and having e.g. antibacterial activity, have beendeveloped.

A pleuromutilin of the present invention includes a pleuromutilin havingthe basic structural elements as set out in formula

wherein R is vinyl or ethyl and the dotted line is a bond or is no bond.

The following numbering system is used in the present application:

The dotted line between positions 19 an 20 (and between positions 1 and2) is a bond or is no bond. In a compound of formula A or of formulaPLEU a hydrogen atom in positions 4, 7 and/or 8 of the ring system maybe replaced by deuterium, and if the dotted line between positions 1 and2 is no bond (single bond between positions 1 and 2) the ring system maybe further substituted in positions 1 and/or 2, e.g. by halogen,deuterium or hydroxy. The group —O— in position 14 is furthersubstituted, preferably by a substituted carbonyl group.

Examples of pleuromutilins according to the present invention includese.g.

-   -   A compound as disclosed in U.S. Pat. No. 3,716,579, e.g. of        formula

-   -    wherein R is CH₃—(CH₂)₇—CH═CH—(CH₂)₇—COO—,        CH₃—(CH₂)₄—CH═CH—CH₂—CH═CH—(CH₂)₇—COO—,        CH₃—(CH₂)₉—CH═CH—(CH₂)₇—COO— or hydrogen;    -   A compound as disclosed in GB1312148, e.g. of formula

-   -    wherein X, Y and Z are as defined in any one of the following        groups:

-   a. X is —CO—CH₂—R₁, wherein R₁ is H, Cl, Br, I, thiocyanato, azido,    (N,N-tetramethylene-thiocarbamoyl)-mercapto, dithiocarbonic    acid-O—(C₁₋₃)alkyl, —S-phenyl, S-phenyl substituted by carboxyl or    by one or two OH, —S-pyridyl, —S-benzyl, —S—(C₁₋₅)alkyl, or    —S—(C₁₋₅)alkyl substituted by one or more amino, OH or carboxyl, Y    is vinyl, and Z is H;

-   b. X is —CO—CO—OH, Y is vinyl and Z is H;

-   c. X is —COCH₃, Y is vinyl and Z is H;

-   d. X is COCH₂NH₂, Y is ethyl and Z is H;

-   e. X is a group of formula

-    Y is ethyl and Z is H-   f. X is H, Y is vinyl and Z is acetyl; or-   g. X is COR₂, wherein R₂ is (C₁₋₅)alkyl, Y is vinyl and Z is H,    -   A compound as disclosed in U.S. Pat. No. 4,278,674, e.g. of        formula

-   -    wherein R₁ is vinyl or ethyl, n is an integer from 2 to 5, X is        sulphur or a group —Y— phenylene-Z— or a group ═NR₄, Y and Z are        both sulphur or one of Y and Z is sulphur and the other is        oxygen, R₄ is H or a second mutilin ring of formula I-U.S. Pat.        No. 4,278,674, wherein R₁ is as defined above and attached via a        —O—CO—CH₂— group in position 14; each of R₂ and R₃ are        (independently of each other) (C₁₋₁₀)alkyl, or R₂ and R₃        together with the nitrogen atom form pyrrolidino, piperidino,        morpholino, thiomorpholino, or 1-hexahydro-1H-azepino, or R₂ and        R₃ together with the nitrogen atom form piperazinyl, the second        nitrogen atom of which is substituted by (C₁₋₅)alkyl,        (C₁₋₄)hydroxyalkyl, (C₂₋₅)alkynoyloxy(C₁₋₄)alkyl, or        benzoyloxy(C₁₋₄)alkyl, or

-   R₁ is as defined above, n=2, R₃ is (C₁₋₁₀)alkyl, (C₁₋₄)hydroxyalkyl,    (C₂₋₅)alkynoyloxy-(C₁₋₄)alkyl, or benzoyloxy(C₁₋₄)alkyl, X is ═NR′₄    and R₂ together with R′₄ forms an ethylene bridge between both    nitorgen atoms; such as    -   14-Desoxy-14[(2-diethylaminoethyl)mercaptoacetoxy]mutilin, e.g.        also known as tiamulin of formula

-   -   A compound as disclosed in U.S. Pat. No. 4,130,709, e.g. of        formula

-   -    wherein R is ethyl or vinyl, R₁ is selected from α- or        β-anomers of hexopyranoses, hexofuranoses, pentopyranoses,        pentofuranoses, pyranose and furanose aminosugars,        disaccharides, trisaccharides and R₂ is H, benzoyl or        (C₂₋₄)alkanoyl; or R₁ is        2-deoxy-2-(hydroxyimino)-3,4,6-tri-O-acetyl-α-D-glucopyranosyl        or -galactopyranosyl,        2-deoxy-2-(hydroxyimino)-α-D-galactopyranosyl,        2-deoxy-2-amino-4,6-di-O-acetyl-α-D-glucopyranosyl, or        2-deoxy-2-acetamido-3,4,6-tri-O-acetyl-α-D-glucopyranosyl and R₂        is H;    -   A compound as disclosed in U.S. Pat. No. 4,129,721; e.g. of        formula

-   -    and the 19,20-dihydro derivative thereof and the tetra        (C₂₋₆)alkanoyl derivatives thereof;    -   A compound as disclosed in EP0013768, e.g. of formula

-   -    wherein R₁ is vinyl or ethyl, m is 0 or 1, and R₂ is a        heterocyclic radical, in which a 5- or 6-membered, unsaturated        or saturated heterocyclic ring containing one or more hetero        atoms selected from O, S and N, is attached to the —S(CH₂)_(m)—        group;    -   A compound as disclosed in EP0153277, e.g. an        N-acyl-14-O-[(1-amino-2-methylpropan-2-yl)thioacetyl]-mutilin or        19,20-dihydromutilin, such as of formula

-   -    wherein R₁ is vinyl or ethyl positions 19 and 20), and R₂ is        optionally hydroxy-substituted aminoalkyl or a 5-membered        saturated heterocycle, e.g. including Valnemulin (Econor®) of        formula

-   -   A compound as disclosed in U.S. Pat. No. 516,526, e.g. of        formula

-   -    wherein R₁ and R₂ independently of each other are H, alkyl,        alkenyl, cycloalkyl, aryl or aralkyl;    -   A compound as disclosed in WO9322288, e.g. of formula

-   -    wherein R₁ and R₂ are independently of each other H, alkyl, or,        R₁ and R₂ together with the carbon atom to which they are        attached are cycloalkyl; and R₃ and R₄ independently of each        other are H, alkyl or substituted alkyl;    -   A compound as disclosed in WO9725309, e.g. of formula

-   -    wherein Y is carbamoyloxy, wherein the N-atom is unsubstituted        or mono- or disubstituted, such as a compound of formula

-   -    wherein R₁ is vinyl or ethyl, R₂ and R₃ independently of each        other are H, or optionally substituted    -   saturated or unsaturated (C₁₋₆)hydrocarbon or (C₃₋₈)cyclic        hydrocarbon,    -   heterocyclyl or aryl, or

-   R₂ and R₃ together form an optionally substituted cyclic group of 3    to 8 ring atoms, optionally containing one additional heteroatom    selected from N, O and S, and optionally fused to a hydrocarbon    ring, a heterocyclic group or an aromatic group; or

-   R₂ is one of the above monovalent groups and R₃ is a group selected    form SO₂R₄, COR₅,

-   OR₅ and NR₆R₇; wherein

-   R₄ is optionally substituted,    -   saturated or unsaturated (C₁₋₆)hydrocarbon or (C₃₋₈)cyclic        hydrocarbon,    -   heterocyclyl, aryl, (C₁₋₆)alkylamino or arylamino;

-   R₅ is optionally substituted    -   saturated or unsaturated (C₁₋₆)hydrocarbon or (C₃₋₈)cyclic        hydrocarbon,    -   heterocyclyl or aryl,

-   R₆ and R₇ independently of each other are H, or optionally    substituted    -   saturated or unsaturated (C₁₋₆)hydrocarbon or (C₃₋₈)cyclic        hydrocarbon,    -   heterocyclyl or aryl, or

-   R₆ and R₇ together with the nitrogen atom to which they are attached    form an optionally substituted (C₃₋₈)cyclic group, optionally    containing one additional heteroatom selected from N, O or S, and    optionally fused to a hydrocarbon ring, a heterocyclic ring or an    aromatic group;    -   A compound as disclosed in WO9805659, e.g. of formula

-   -    wherein R₁ is vinyl or ethyl, and R₂ is a group R₃, R₄CH₂—, or        R₅R₆CH═CH—, wherein, each of R₃ and R₄ is an azabicyclic ring        system, or R₅ and R₆ together with the carbon atom to which they        are attached form an azabicyclic ring system;    -   A compound of WO9821855; e.g. of formula

-   -    wherein n and m are independently of each other 0, 1 or 2; X is        O, S, S(O), SO₂, —COO—, —NH—,—CONH—, —NHCONH—, or a bond; R₁ is        vinyl or ethyl; R₂ is a non-aromatic monocyclic or bicyclic        group containing one or two basic nitrogen atoms and attached        through a ring carbon atom, e.g. R₂ is optionally substituted        quinuclidinyl, azabicyclo[2.2.1]heptyl, azabicyclo[4.3.0]nonyl,        azabicyclo[3.2.1]octyl, azabicyclo[3.3.0]octyl,        azabicyclo[2.2.2]octyl, azabicyclo[3.2.1]octenyl,        azabicyclo[3.3.1]nonyl or azabicyclo[4.4.0]decyl; R₃ is H, OH;        or the moietity R₂(CH₂)_(m)X(CH₂)_(n)CH₂COO at position 14 of IA        or IB is replaced by R_(a)R_(b)C═CHCOO, wherein one of R_(a) or        R_(b) is hydrogen and the other is R₂; or R_(a) and R_(b)        together form R₂;    -   A compound as disclosed in WO0007974, e.g. a 14-acyloxy        derivative of mutilin or 19,20-dihydromutilin having a 2-fluoro        substituent, such as of formula

-   -    wherein R₁ is vinyl or ethyl (positions 19 and 20), and        R₂COO—is acyloxy, e.g. HOCH₂CO₂— or R—X—CH₂CO₂, wherein X is O,        S or NR′ and R and R′ are indpendently of each other an        aliphatic or aromatic group, preferably R₂COO— is a carbamoyl        group, such as a group R₃R₄NCO₂— wherein R₃ and R₄ have various        meanings (e.g. R₃ and R₄ have the meaning as disclosed for the        meaning of R₂ and R₃ in WO9725309);    -   A compound as disclosed in WO0027790, e.g. a compound of formula

-   -    wherein R₁ is a R^(A)(CH₂)_(n)O(CH₂)_(m), R^(A)(CH₂)_(p), or a        group of formula

-   -    wherein R is a spiro-fused mono- or bicyclic ring containing        one or two basic N-atoms; X₁ and X₂ which may be the same or        different, are each —CH₂— or —C═O, provided that at least one of        X₁ and X₂ is —C═O; and Y is —NH—, —CH₂— or —CH₂—CH₂—;

-   R^(A) is an optionally substituted aryl group or heteroaryl group    linked via a carbon atom;

-   e.g. R^(A) is optionally substituted phenyl, thienyl, pyridinyl,    furyl, thiazolyl, isoxazolyl, benzimidazolyl, quinolinyl,    1,2,3,4-tetrahydro-isoquinolinyl or benzthiazolyl:

-   m is 1, 2 or 3; n is 0, 1 or 2; p is 1 to 4; R₂ is vinyl or ethyl;    and R₃ is H, OH or F, and R₄ is H; or R₃ is H and R₄ is F;    -   A compound as disclosed in WO0037074, e.g. a compound of formula

-   -    wherein R₁ is an optionally substituted heteroaryl group which        comprises a 5-membered heteroaromatic ring which has at least        one N-atom, e.g. a pyrrole, pyrazole, imidazole, 1,2,3-triazole,        1,2,4-triazole, indole, benzimidazole, benzotriazole,        2-aza-indole or 6-aza-indole; and which is linked via a N-atom;        R₂ is vinyl or ethyl; R₃ is H, OH or F, and R₄ is H; or R₃ is H        and R₄ is F;    -   A compound as disclosed in WO0073287, e.g. a compound of formula

-   -    wherein R₁ is optionally substituted aryl, e.g.        azabicyclo-octyl; or an optionally substituted nitrogen        containing ring, e.g. piperidinyl; R₂ is vinyl or ethyl; R₃ is        H, OH or F and R₄ is H; or

-   R₃ is H and R₄ is F;    -   A compound as disclosed in WO0114310, e.g. a compound of formula

-   -    wherein R₁ is a nitrogen containing heterocycle, an optionally        substituted aryl or optionally subsituted heteroaryl, or CH₂R₅,

-   e.g. R₁ is optionally substituted phenyl, 3-pyridyl, 4-pyridyl,    pyrimidin-2-yl, 1,3,4-thiadiazol-2-yl, benzothiazol-2-yl.    2H-1,2,4-triazol-3-yl, azabicycloheptyl, azabicyclooctyl or    piperidinyl;

-   R₂ is vinyl or ethyl; R₃ is H, OH or F and R₄ is H; or R₃ is H and    R₄ is F; R₅ is halogen or SR₆; and R₆ is aminoalkyl, a nitrogen    containing heterocycle, or an optionally substituted aryl or    optionally subsituted heteroaryl; e.g. R₆ is optionally substituted    phenyl, 3-pyridyl, 4-pyridyl, pyrimidin-2-yl, 1,3,4-thiadiazol-2-yl,    benzothiazol-2-yl. 2H-1,2,4-triazol-3-yl, azabicycloheptyl,    azabicyclooctyl or piperidinyl;    -   A compound as disclosed in WO0109095, e.g. a compound of formula

-   -    wherein R is hydrogen or alkyl; R₁ is hydrogen or a group of        formula

-   -    wherein X is S, O, or NR₁₀, wherein R₁₀ is H or alkyl, or        N⁺(R′₁₀)₂ wherein R′₁₀ is alkyl in the presence of an        appropriate anion; and R₉ is amino, alkyl, aryl, heterocyclyl or        mercapto; and, if X is oxygen, R₉ is additionally hydrogen; R₂        is arylene, e.g. phenylene; or heterocyclene; R₄ is hydrogen or        alkyl; R₅ is hydrogen or alkyl; R₃, R₃′, R₆, R₇ and R₈        independently of each other are hydrogen or deuterium; or R and        R₂ together with the nitrogen atom to which they are attached        form non-aromatic heterocyclene and R₁ is a group of formula

-   -    wherein X and R₉ are as defined above; e.g. a compound of        formula

-   -    wherein R_(1s) is hydrogen or a group of formula

-   -    wherein R_(6s) is hydrogen or deuterium; R_(2s) is hydrogen,        methyl or tert-butyl;

-   R_(7s) is hydrogen or methyl; and R_(3s), R_(4s) and R_(5s) are    hydrogen or deuterium;    -   A compound as disclosed in WO0174788, e.g. a compound of formula

-   -    wherein R₁ is a 5- or 6-membered optionally substituted        heteroaryl group;

-   e.g. pyridine, pyridazine, pyrimidine, pyrazine, isoxazole,    thiazole, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole,    benzimidazole, 3-oxo-3,4-dihydropyrido[2,3-b]pyrazine, or    pyrazolo[1,5-a]pyrimidine; and R₂ is vinyl or ethyl;    -   A compound as disclosed in WO0204414, e.g. a compound selected        from 14-O-[(cycloalkyl-sulfanyl)acetyl]mutilins;        14-O-[(cycloalkyl-alkyl-sulfanyl)acetyl]mutilins;        14-O-[(cycloalkoxy)acetyl]mutilins; or        14-O-[(cycloalkyl-alkoxy)acetyl]mutilins, such as of formula

-   -    wherein R is hydrogen; R₁ is hydrogen or a group of formula

-   -    wherein X is sulphur, oxygen or NR₁₀, wherein R₁₀ is hydrogen        or alkyl; and R₉ is amino, alkyl, aryl or heterocyclyl; and, if        X is oxygen, R₉ is additionally hydrogen; Y is sulphur or        oxygen; R₂ is hydrogen or one or more substituents, R₄ is        hydrogen or alkyl; R₅ is hydrogen or alkyl; R₃ and R₃′ are        hydrogen, deuterium, or halogen; R₆, R₇ and R₈ are hydrogen or        deuterium; m is a number selected from 0 to 4; n is a number        selected from 0 to 10; and p is a number selected from 0 to 10;        with the proviso that n plus p are at least 1;

-   e.g. a compound of formula

-   -    wherein R_(1p) is hydrogen or the residue of an amino acid;    -   A compound as disclosed in WO0212199, e.g. a compound of formula

-   -    wherein R₁ is:    -   a 5- or 6-membered aromatic or heteroaromatic ring attached via        a ring carbon atom, preferably pyridyl, and comprising a        substituent selected from halo, R₇O—, R₇S— or R₈R₉N— on a ring        carbon adjacent to the carbon of attachment; or    -   a 5- or 6-membered dihydro heteroaromatic ring attached via a        ring carbon atom and comprising one oxygen or one or two        nitrogen atoms and optionally fused to phenyl, a 5- or        6-membered heteroaryl ring comprising one or two nitrogen atoms        or a 5- or 6-membered heterocyclyl ring comprising a sulphur,        oxygen or nitrogen atom and further comprising a substituent        selected from oxo or thioxo on a ring carbon adjacent to the        carbon of attachment;    -   a 6-membered tetrahydro heteroaromatic ring attached via a ring        carbon atom comprising one or two nitrogen atoms and further        comprising two substituents independently selected from oxo or        thioxo wherein one of the substituents is on a ring carbon        adjacent to the carbon of attachment; or    -   a bicyclic heteroyaryl ring attached via a ring carbon atom and        comprising nine or ten ring atoms and from one to four nitrogen        atoms;

-   wherein the ring of R₁ may be optionally further substituted; R₂ is    vinyl or ethyl; R₃ is H, OH or F and R₄ is H, or R₃ is H and R₄ is    F; and R₅ and R₆ together form an oxo group; or R₃ and R₄ is each H    and R₅ is H, or OH and R₆ is H, or R₅ is H and R₆ is H or OH; R₇ is    optionally substituted (C₁₋₆)alkyl; and R₈ and R₉ are independently    selected from hydrogen or optionally substituted (C₁₋₆)alkyl.    -   A compound as disclosed in WO0222580, of formula

-   -    wherein R and R₂ together with the nitrogen atom to which they        are attached form pyrrolidinyl or piperidinyl, R₁ is a group of        formula

-   -   R₃ and R′₃ are hydrogen, deuterium or halogen, R₄ is hydrogen or        alkyl, R₅ is hydrogen or alkyl, R₆, R₇ and R₈ are hydrogen or        deuterium; R₉ is amino, alkyl, aryl, heterocyclyl or mercapto;        and, if X is oxygen, R₉ is additionally hydrogen; R₁₀ is        hydrogen or alkyl, R′₁₀ is alkyl, X is sulphur, oxygen, NR₁₀, or        N⁺(R′₁₀)₂ in the presence of an appropriate anion, Y is sulphur        or oxygen, and m is 0, 1 or 2;

-   with the proviso that, when R and R₂ together with the nitrogen atom    to which they are 10 attached form piperidinyl, m is 0, Y is S and Y    is attached in position 3 of said piperidine ring that group of    formula I which is attached to the piperidine ring via the residue Y    is either in the (S)-configuration or in the (R)-configuration,    preferably in the (S)-configuration; preferably a compound of    formula

-   -    wherein R_(3p), R′_(3p), R_(6p), R_(7p) and R_(8p) are,        index-number correspondingly, as defined for a compound of        formula I-WO0222580 for R₃, R′₃, R₆, R₇ and R₈; and R_(5p) is        hydrogen or one or more substituents, and if the group attached        to the piperidine ring via the sulphur atom is In position 3 of        said piperidine ring and R_(5p) is hydrogen, then the group        attached to the sulphur atom is either in the (S)-configuration        or in the (R)-configuration;

-   a compound of formula

-   -    wherein R_(3q), R′_(3q), R_(6q), R_(7q) and R_(8q) are,        index-number correspondingly, as defined for a compound of        formula I-WO0222580 for R₃, R′₃, R₆, R₇ and R₈; R_(5q) is        hydrogen or one or more substituents, preferably hydrogen; and        R_(q) is that part of an amino acid which remains if the        carboxylic group is splitt off;

-   a compound of formula

-   -    wherein R_(3r), R′_(3r), R_(4r), R_(6r), R_(7r) and R_(8r) are,        index-number correspondingly, as defined for a compound of        formula WO0222580 for R₃, R′₃, R₄, R₆, R₇ and R₈; R_(5r) is        hydrogen or one or more substituents, and R_(1r) is that part of        an amino acid which remains if the carboxylic group is splitt        off, or a compound of formula

-   -    wherein R_(3s), R′_(3s), R_(4s), R_(6s), R_(7s) and R_(8s),        respectively, are, index-number correspondingly, as defined for        a compound of formula I-WO0222580 for R₃, R′₃, R₄, R₆, R₇ and        R₈;

-   R_(5s) is hydrogen or one or more substituents, preferably hydrogen;    and R_(1s) is that part of an amino acid which remains if the    carboxylic group is splitt off; e.g. wherein in a compound of    formula I_(s) the group attached to the piperidine ring via the    sulphur atom is either in the (S)-configuration or in the    (R)-configuration; e.g. wherein in a group R_(1s) the amine group of    the amino acid residue is either in the (S)-configuration or in the    (R)-configuration;    -   A compound which is selected from the group consisting of        compounds of formulae

-   -    wherein R_(EX) is as set out in TABLE 1 (in all Examples of        TABLE 1 the compounds are of formula I_(EX), with the exception        of Example 12 in which the compound is of formula I′_(EX);        ¹H-NMR-data of the compounds described and obtained according,        e.g. analogously, to a method as described in the examples, are        also indicated in TABLE 1):

TABLE 1

Example 1 14-O-[4-Amino-cyclohexan-1-yl-sulfanyl)-acetyl]-mutilin in theform of a hydrochloride (d₆-DMSO): 7.9(b, 3H, NH₃),AB-system(ν_(A)=3.23, ν_(B)=3.29, 2H, H₂₂, J=15.2Hz), 3.03(m, 1H, SCH),3.10(m, 1H, CHN)

Example 214-O-[(2-(R*)-((R)-Histidinyl)-amino-cyclohexan-1-(S*)-yl)-sul- fanylacetyl)]-mutilin in the form of a hydrochloride (d₆-DMSO):Diastereoisomers: 8.4, 9.0(2xm, 2H, NH), 7.5, 8.7 (2xb, 2H, imidazole),6.15, 5.1(2xm, H₁₉, H₂₀, H₂₁), 5.52(d, 1H, J=5.2Hz, H₁₄), 4.2(m, 1H,a-H-histidine)3.45(m, 1H, H₁₁), 3.3(m, 2H, H₂₂), 2.7(m, 1H, CHS), 1.18,1.45(2xs, (CH3)₁₅, (CH3)₁₈), 0.75, 0.88(2xd, (CH₃)₁₆, (CH₃)₁₇, J=5.4Hz)

Example 3a 14-O-[(2-(R*)-Methylamino-cyclohexan-1-(S*)-yl)-sulfanylacetyl)]-mutilin (d₆-DMSO): Diastereoisomers: 6.15, 5.1(2xm, H₁₉, H₂₀,H₂₁), 5.52(d, 1H), J=5.2Hz, H₁₄), 4.50(d, 1H, OH, J=5Hz), 3.45(t, 1H,H₁₁, J=5Hz), 3.25(m, 2H, H₂₂), 3.25(m, 1H, CHN), 2.82(m, 1H, CHS),2.38(d, 3H, CH₃NH, J=5.1Hz), 1.3, 1.34)1.18, 1.45(2xs, (CH3)₁₅,(CH3)₁₈), 0.75, 0.88(2xd, (CH₃)₁₆, (CH₃)₁₇, J=5.4Hz).

Example 3b 14-O-[(2-(R*)-Methylamino-cyclohexan-1-(R*)-yl)-sulfanylacetyl)]-mutilin (d₆-DMSO): Diastereoisomers: 6.15, 5.1(2xm, H₁₉, H₂₀,H₂₁), 5.52(d, 1H, J=5.2Hz, H₁₄), 4.50(d, 1H, OH, J=5Hz), 3.45(t, 1H,H₁₁, J=5Hz), 3.25(m, 2H, H₂₂), 3.25(m, 1H, CHN), 2.65(m, 1H, CHS),2.43(d, 3H, CH₃NH, J=5.1Hz), 1.3, 1.34)1.18, 1.45(2xs, (CH3)₁₅,(CH3)₁₈), 0.75, 0.88(2xd, (CH₃)₁₆, (CH₃)₁₇, J=5.4Hz)

Example 4 (14-O-[4-((R)-Valyl-amino-cyclohexane-1-yl)-sulfanyl)-ace-tyl]-mutilin in the form of a hydrochloride (CD₃OD): 8.3(d, 1H, NH),8.1(b, 3H, NH3), 6.15(m, 1H, H19), 5.55(d, 1H, H14), 5.05(m, 2H, H20),3.75(m, 1H, NCHCO), 3.3(m, 1H, NCH), 3.42(d, 1H, H11), 3.25(m, 2H,SCH₂CO), 2.98(m, 1HCHS), 0.9(d, 6H, (CH₃)₂CH), 1.08, 1.36(2xs, 6H,(CH₃)₁₈, (CH₃)₁₅), 0.65, 0.83(2xd, 6H, (CH₃)₁₆, (CH₃)₁₇)

Example 5a14-O-[((3-(R*)-Amino-cycloheptan-1(R*)-yl)sulfanyl)acetyl]-mu- tilin and14-O-[((3-(S*)-amino-cycloheptan-1(S*)-yl)-sul- fanyl)-acetyl]mutilin inthe form of a hydrochloride (diastereoisomeric mixture) (d₆-DMSO):8.0(b, 3H, NH₃ ⁺), 6.15, 5.1(2xm, H₁₉, H₂₀, H₂₁), 5.52(d, 1H, J=5.2Hz,H₁₄), 3.1, 3.2(2xm1H, CHNH₃ ⁺), 3.4(m, 1H, H₁₁,), 3.3(m, 2H, H₂₂),2.9(m, 1H, SCH), 1.18, 1.45(2xs, (CH3)₁₅, (CH3)₁₈), 0.9(m, 6H,CH(CH₃)₂), 0.75, 0.88(2xd, (CH₃)₁₆, (CH₃)₁₇, J=5.4Hz) Example 5b14-O-[((3-(R*)-Amino-cycloheptan-1(S*)-yl)sulfanyl)acetyl]-mu- tilin and14-O-[((3-(S*)-Amino-cycloheptan-1(R*)-yl)sul- fanyl)acetyl]-mutilin inthe form of a hydrochloride (diastereoisomeric mixture) (d₆-DMSO):7.8(b, 3H, NH₃ ⁺), 6.15, 5.1(2xm, H₁₉, H₂₀, H₂₁), 5.52(d, 1H, J=5.2Hz,H₁₄), 3.15(2xm1H, CHNH₃ ⁺), 3.4(m, 1H, H₁₁,), 3.3(m, 2H, H₂₂), 2.95(m,1H, SCH), 1.18, 1.45(2xs, (CH3)₁₅, (CH3)₁₈), 0.9(m, 6H, CH(CH₃)₂), 0.75,0.88(2xd, (CH₃)₁₆, (CH₃)₁₇, J=5.4Hz)

Example 6 14-O-[(3-(R/S)-(R)-Valylamino-1-(R/S)-yl)sul-fanyl)acetyl]mutilin in the form of a hydrochloride (d₆-DMSO): 8.4(m,1H, NHC═O), 8.1(b, 3H, NH₃ ⁺), 6.15, 5.1(2xm, H₁₉, H₂₀, H₂₁), 5.52(d,1H, J=5.2Hz, H₁₄), 3.5, 3.9(2xm, 1H, a-H-va- lyl), 3.15(2xm1H, CHNH₃ ⁺),3.4(m, 1H, H₁₁,)₂ 3.3(m, 2H, H₂₂), 2.95(m, 1H, SCH), 1.18, 1.45(2xs,(CH3)₁₅, (CH3)₁₈), 0.9(m, 6H, CH(CH₃)₂), 0.75, 0.88(2xd, (CH₃)₁₆,(CH₃)₁₇, J=5.4Hz)

Example 7 14-O-[(3-(R/S)-Guanidino-cyclohexan-1-(R/S)-yl)-acetyl]mutilinin the form of a hydrochloride (d₆-DMSO): 6.8-7.4(b, 3H, NH₃ ⁺), 7.65,7.7(2xm, 1H, NH), 6.15, 5.1(2xm, H₁₉, H₂₀, H₂₁), 5.52(d, 1H, J=5.2Hz,H₁₄), 4.5(d, 1H, OH, J=6Hz), 3.1(m1H, CHNH), 3.4(t, 1H, H₁₁, J=6Hz),3.3(m, 2H, H₂₂), 2.7(m, 1H, SCH), 1.18, 1.45(2xs, (CH3)₁₅, (CH3)₁₈),0.75, 0.88(2xd, (CH₃)₁₆, (CH₃)₁₇, J=5.4Hz)

Example 8a14-O-[3-(R*)-((R)-Valyl-amino-cyclopentan-1-(S*)-yl)-sulfanyl)-ace-yl]-mutilin in the form of a hydrochloride (DMSO-d₆): 8.5(d, 1H, NH,J=7.2Hz), 8.1(bs, 3H, NH₃ ⁺), 6.15, 5.06, 5.02(3xm, H₁₉, H₂₀, H₂₁),5.55(d, 1H, H₁₄, J=8.2Hz), 4.05(m, 1H, H-alpha-valyl), 3.15(m, 1H,H-1′), 3.2-3.5(m, H-3′, H₁₁, H₂₂), 1.35, 1.05(2xs, (CH₃)₁₅, (CH₃)₁₈),0.91, 0.88(d, (CH₃)₂CH, J=6.8Hz), 0.8, 0.62(2xd, (CH₃)₁₆, (CH₃)₁₇,J=6.8Hz) Example 8b14-O-[3-(S*)-((R)-Valyl-amino-cyclopentan-1-(R*)-yl)-sulfanyl)-ace-tyl]-mutilin in the form of a hydrochloride (DMSO-d₆): 8.5(d, 1H, NH,J=7.2Hz), 8.1(bs, 3H, NH₃ ⁺), 6.15, 5.06, 5.02(3xm, H₁₉, H₂₀, H₂₁),5.55(d, 1H, H₁₄, J=8.2Hz), 4.05(m, 1H, H□-valyl), 3.15(m, 1H, H-1′),3.2-3.5(m, H3′, H₁₁, H₂₂), 1.35, 1.05(2xs, (CH₃)₁₅, (CH₃)₁₈), 0.91,0.89(d, (CH₃)₂CH, J=6.9Hz), 0.8, 0.62(2xd, (CH₃)₁₆, (CH₃)₁₇, J=6.8Hz).Example 8c14-O-[3-(S*)-((R)-Valyl-amino-cyclopentan-1-(S*)-yl)-sulfanyl)-ace-tyl]-mutilin and 14-O-[3-(R*)-((R)-valyl-amino-cyclopentan-1-(R*)-yl)-sulfanyl-acetyl]-mutillin in the form of ahydrochloride(mixture of trans-diastereoisomers) (DMSO-d₆): 8.52,8.53(2xd, 1H, NH, J=6.9Hz), 8.1(bs, 3H, NH₃ ⁺), 6.15, 6.12, 5.0-5.1(6xm,H₁₉, H₂₀, H₂₁), 5.54, 5.55(2xd, 1H, H₁₄, J=8.2Hz), 4.15(m, 1H,H□-valyl), 3.1-3.5(m, H-1′, H3′, H₁₁, H₂₂), 1.35, 1.05(2xs, (CH₃)₁₅,(CH₃)₁₈), 0.91, 0.88(d, (CH₃)₂CH, J=6.8Hz), 0.8, 0.62(2xd,(CH₃)₁₆(CH₃)₁₇, J=6.8Hz)

Example 914-O-[((3-(R/S)-Amino-cyclopentyl)-sulfanyl)-acetyl]-mutilin-hydro-chloride (DMSO-d₆): 8.03(bs, 3H, NH₃ ⁺), 6.13, 5.05(2xm, 3H, H₁₉, H₂₀,H₂₁), 5.55(d, 1H, H₁₄, J=8.0Hz), 3.2-3.6(m, H-3′, H₁₁, H₂₂), 3.14(m, 1H,H-1′), 1.35, 1.05(2xs, (CH₃)₁₅, (CH₃)₁₈), 0.8, 0.62(2xd, (CH₃)₁₆,(CH₃)₁₇, J=6.8Hz)

Example 1014-O-[(2-(R*)-((R)-Valyl)-methylamino-cyclohexan-1-(R*)-yl)-sul- fanylacetyl)]-mutilin in the form of a hydrochloride (d₆-DMSO):Diastereoisomers: 8.0(m, 3H.NH₃ ⁺), 6.15, 5.1(2xm, H₁₉, H₂₀, H₂₁),5.52(d, 1H, J=5.2Hz, H₁₄), 4.50(m, 1H, OH), 4.2(m, 1H, a-H-val- ine),3.45(m, 1H, H₁₁), 3.25(m, 2H, H₂₂), 3.25(m, 1H, CHN), 2.82(m, 1H, CHS),2.88, 2.94(2xs, 3H, CH₃N), 1.3, 1.34), 1.18, 1.45(2xs, (CH3)₁₅,(CH3)₁₈), 0.75, 0.88, (2xd, (CH₃)₁₆, (CH₃)₁₇, J=5.4Hz)

Example 11 14-O-[(3-Guanidino-phenylsulfonyl)-acetyl]mutilin in the formof a hydrochloride (CDCl₃): 0.58(d, 3H, H₁₆, J=7.2Hz), 0.81(d, 3H, H₁₇,J=7.3Hz), 1.02(s, 3H, H₁₈), 1.32(s, 3H, H₁₅), ABX-system(ν_(A)=1.2,ν_(B)=1.88, H_(13a), H_(13b), J=16.1Hz, J=9.1Hz), 2.08(d, 1H, H₄,J=2.1Hz), ABXY-sys- tem(ν_(A)=2.23, ν_(B)=2.19, H_(2a), H_(2b),J=16.2Hz, J=9.1Hz, J=1.8Hz), 2.3(m, 1H, H₁₀), 3.4(d, 1H, H₁₁, J=5.98Hz),AB-system(ν_(A)=3.81, ν_(B)=3.89, 2H, H₂₂, J=14.1Hz), 5.18(dd, 1H,H_(20a), J=17.5Hz, J=1.6Hz), 5.29(dd, 1H, H_(20b), J=11Hz, J=1.6Hz),5.51(d, 1H, H₁₄, J=8.3Hz), 6.05(dd, 1H, H₁₉, J=11Hz, J=17.5Hz), 7.0(m,1H, arom.H), 7.18(m2H, arom.H), 7.3t, 1H, arom, H₅, J=8Hz)

Example 1214-O-[(N-(3-Methyl-2(R)-amino-butyryl)-piperidine-3(S)-yl)-sulfanyl-acetyl]-2(S)-fluoro-mutilin in the form of a hydrochloride (DMSO-d₆):Rotamers: 7.95(bs, 3H, NH₃ ⁺), 6.12, 5.05(2xm, H₁₉, H₂₀, H₂₁), 5.56,5.52(2xd, 1H, H₁₄, J=8.3Hz), 4.92(ddd, 1H, H₂, J=51.3, 8.4, 8.0Hz), 4.7,4.69(2xd, 1H, 11-OH, J=6.1Hz), 4.06(m, 1H, H□-valyl), 4.3, 4.25, 3.91,3.88, 2.6-3.6(m, 4xCH₂N, SCH, H₁₁, H₂₂), 1.39, 1.06(2xs, (CH₃)₁₅,(CH₃)₁₈), 0.99, 0.9, 0.84, 0.64(4xd, (CH₃)₂CH, (CH₃)₁₆, (CH₃)₁₇,J=6.8Hz)

Example 13 14-O-[((Piperidin-3(S)-yl)methyl-sulfanyl)-acetyl]-mutilin inthe form of a hydrochloride (d₆-DMSO, 350K): 6.15, 5.05(2xm, H₁₉, H₂₀,H₂₁), 5.55(d, 1H, 5.2Hz, H₁₄), 3.4(d, 1H, H₁₁, J=5.2Hz), 3.05, 2.95,2.52, 2.31, 2.09, (5xm, 4H, CH₂NCH₂), 3.2(m, 2H, SCH₂C═O), 2.48(m, 2H,CHCH₂S), 1.18, 1.45(2xs, (CH3)₁₅, (CH3)₁₈), 0.75, 0.88, (2xd, (CH₃)₁₆,(CH₃)₁₇, J=5.4Hz)

Example 14 14-O-[((Azepan-4-(R/S)-yl)-sulfanyl acetyl)]-mutilin in theform of a hydrochloride 400mg of14-O-[((N-BOC-azepan-4-(R/S)-yl)-sulfanyl acetyl)-mu- tilin(d₆-DMSO):8.2-8.5(b, 2H, NH₂ ⁺), 6.15, 5.1(2xm, H₁₉, H₂₀, H₂₁), 5.52(d, 1H,J=5.2Hz, H₁₄), 4.52(d, 1H, OH, J=6.2Hz)3.4(t, 1H, H₁₁, J=6.2Hz), 3.3(m,2H, H₂₂), 2.9-3.2(2xm, 3H, SCH, CHNCH), 1.18, 1.45(2xs, (CH3)₁₅,(CH3)₁₈), 0.75, 0.88(2xd, (CH₃)₁₆, (CH₃)₁₇, J=5.4Hz

Example 15 14-O-[((N-(R)-Valyl-azepan-4-(R/S)-yl)-sulfanylacetyl)]-mutilin-hy- drochloride (d₆-DMSO): 7.7-8.0(b, 3H, NH₃ ⁺), 6.15,5.1(2xm, H₁₉, H₂₀, H₂₁), 5.52(d, 1H, J=5.2Hz, H₁₄), 4.52(d, 1H, OH,J=6.2Hz), 3.4(t, 1H, H₁₁, J=6.2Hz), 4.1(m, α-H-valine), 3.4, 2.6(2xm,4H, CH₂NCH₂)3.3(m, 2H, H₂₂), 2.9 (m, 1H, SCH), 1.18, 1.45(2xs, (CH₃)₁₅,(CH₃)₁₈), 0.75, 0.88(2xd, (CH₃)₁₆, (CH₃)₁₇, J=5.4Hz)

Example 1614-O-[(N-(R)-Valyl-pyrrolidin-3(s)-yl)-sulfanyl-acetyl]-mutilin-hy-drochloride (CD₃OD): Rotamer, 8.1(b, 3H, NH3), 6.3-6.4(m, 1H, H19),5.75(d, 1H, H14), 5.15(m, 2H, H20), 4.15(m, 1H, NCHCO), 3.9(m, 1H, NCH),3.6(m, 1H, NCH), 3.42(d, 1H, H11), 3.28-3.35(m, 2H, SCH₂CO), 0.95,0.98(2xd, 6H, (CH₃)₂CH), 1.08, 1.36(2xs, 6H, (CH₃)₁₈, (CH₃)₁₅), 0.65,0.83(2xd, 6H, (CH₃)₁₆, (CH₃)₁₇)

Example 1714-O-[((N-(R)-Pipecolyl-piperidin-4-yl)methyl-sulfanyl)-acetyl]-mutilinin the form of a hydrochloride ¹H-NMR(d₆-DMSO, 350K): 6.15, 5.05(2xm,H₁₉, H₂₀, H₂₁), 5.55(d, 1H, 5.2Hz, H₁₄), 3.35(d, 1H, H₁₁, J=5.2Hz),4.3(m, α-H-pipecol), 4.2, 4.05, 3.75(4xm, CH₂NCH₂), AB-system: 3.12,3.18, J=14.7Hz, H₂₂),), 2.8(m, 1H, SCH), 1.18, 1.45(2xs, (CH3)₁₅,(CH3)₁₈), 0.75, 0.88(2xd, (CH₃)₁₆, (CH₃)₁₇, J=5.4Hz)

-   -   A compound of formula

wherein

-   -   the dotted line is a bond (double bond between positions a=b),        R_(1A) is hydrogen and R_(2A) is not present,        or    -   the dotted line is no bond (single bond between positions a-b).        and R_(1A) and R_(2A) independently of each other are hydrogen,        halogen or deuterium,

-   R_(3A) is (C₁₋₆)alkyl,

-   R_(4A) is hydrogen, (C₁₋₆)alkyl, a group —C(═NH)—NH₂, or the residue    of an amino acid,

-   R_(5A) is hydrogen, or

-   R_(4A) and R_(5A) together are a group ═CH—NH₂,

-   R_(6A) is hydrogen or deuterium, and

-   m_(A) is 0, 1, 2, 3, 4, or 5;

-   e.g. preferably the dotted line is no bond; R_(1A) is hydrogen,    R_(2A) is hydrogen, R_(3A) is (C₁₋₄)alkyl, such as methyl, R_(4A)    and R_(5A) are as defined above, R_(6A) is hydrogen, and m_(A) is 2,    3 or 4;

-   e.g. including pleuromutilins, which are selected from the group    consisting of compounds of formula I_(X), wherein R_(EX) is as set    out in TABLE 2 (¹H-NMR-data of the compounds described and obtained    according, e.g. analogously, to a process as described in the    examples are also indicated in TABLE 2):

TABLE 2

Example 18

Example 18a14-O-[(3-(R*)-Amino-1-methyl-cyclopentan-1-(R*)-yl)-sulfanyl)-ace-tyl]-mutilin and14-O-[(3-(S*)-amino-1-methyl-cyclopentan-1-(S*)-yl)-sul-fanyl)-acetyl]-mutilin in the form of a hydrochloride(mixture oftrans-diastereoisomers) (DMSO-d₆): 7.98(bs, 3H, NH₃ ⁺), 6.13, 5.06,5.03(3xm, H₁₉, H₂₀, H₂₁), 5.55(d, 1H, H₁₄, J=8.2Hz), 3.56(m, 1H, H-3′),3.3-3.3(m, H₁₁, H₂₂), 1.36, 1.30, 1.29, 1.05(4xs, 9H, CH₃CS, (CH₃)₁₅,(CH₃)₁₈), 0.8, 0.62(2xd, (CH₃)₁₆, (CH₃)₁₇, J=6.9Hz)

Example 18b14-O-[(3-(R*)-Amino-1-methyl-cyclopentan-1-(S*)-yl)-sulfanyl)-ace-tyl]-mutilin and14-O-[(3-(S*)-Amino-1-methyl-cyclopentan-1-(R*)-yl)-sul-fanyl)-acetyl]-mutilin in the form of a hydrochloride(mixture ofcis-diastereoisomers) (DMSO-d₆): 8.03(bs, 3H, NH₃ ⁺), 6.13, 5.06,5.03(3xm, H₁₉, H₂₀, H₂₁), 5.53(d, 1H, H₁₄, J=8.0Hz), 4.52(bs, 1H-11-OH),3.51(m, 1H, H-3′), 3.2-3.4(m, H₁₁, H₂₂), 1.41, 1.40, 1.35, 1.05(4xs, 9H,CH₃CS (CH₃)₁₅, (CH₃)₁₈), 0.8, 0.62(2xd, (CH₃)₁₆, (CH₃)₁₇, J=6.9Hz)

Example 19

Example 19a14-O-{[(1S*,3S*)-3-((R)-2-Amino-3-methyl-butyrylamino)-1-meth-yl-cyclopentylsulfanyl]-acetyl}-mutilin in the form of a hydrochlorideRotamer 1: (DMSO-d₆): 8.48(d, 1H, NH, J=7.1Hz), 8.1(bs, 3H, NH₃ ⁺),6.11, 5.06, 5.03(3xm, H₁₉, H₂₀, H₂₁), 5.55(d, 1H, H₁₄, J=8.5Hz), 4.15(m,1H, H□-valyl), 3.1-3.5(m, H-1′, H-3′, H₁₁, H₂₂), 1.35, 1.32, 1.05(3xs,CH₃CS, (CH₃)₁₅, (CH₃)₁₈), 0.91, 0.88(d, (CH₃)₂CH, J=6.8Hz), 0.8,0.62(2xd, (CH₃)₁₆, (CH₃)₁₇, J=6.8Hz). Rotamer 2: (DMSO-d₆): 8.48(d, 1H,NH, J=7.1Hz), 8.1(bs, 3H, NH₃ ⁺), 6.11, 5.06, 5.03(3xm, H₁₉, H₂₀, H₂₁),5.55(d, 1H, H₁₄, J=8.5Hz), 4.5(bs, 1H, 11-OH), 4.15(m, 1H, H□-valyl),3.1-3.5(m, H-1′, H-3′, H₁₁, H₂₂), 1.35, 1.32, 1.05(3xs, CH₃CS, (CH₃)₁₅,(CH₃)₁₈), 0.91, 0.88(d, (CH₃)₂CH, J=6.8Hz), 0.8, 0.62(2xd, (CH₃)₁₆,(CH₃)₁₇, J=6.8Hz)

Example 19b14-O-{[(1R*,3R*)-3-((R)-2-Amino-3-methyl-butyrylamino)-1-meth-yl-cyclopentylsulfanyl]-acetyl}mutilin-hydrochloride (DMSO-d₆):Rotamers: 8.53(d, 1H, NH, J=7.2Hz), 8.1(bs, 3H, NH₃ ⁺), 6.12, 5.06,5.03(3xm, H₁₉, H₂₀, H₂₁), 5.55(d, 1H, H₁₄, J=8.4Hz), 4.52(d, 1H, 11-OH,J=6.1Hz), 4.25(m, 1H, H□-valyl), 3.2-3.5(m, H-1′, H-3′, H₁₁, H₂₂), 1.42,1.39, 1.35, 1.05(4xs, 9H, CH₃CS, (CH₃)₁₅, (CH₃)₁₈), 0.91, 0.88(d,(CH₃)₂CH, J=6.8Hz), 0.8, 0.62(2xd, (CH₃)₁₆, (CH₃)₁₇, J=6.8Hz)

Example 19c14-O-{[(1R*,3S*)-3-((R)-2-Amino-3-methyl-butyrylamino)-1-meth-yl-cyclopentylsulfanyl]-acetyl}-mutilin and14-O-{[(1S*,3R*)-3-((R)-2-Amino-3-methyl-butyrylamino)-1-meth-yl-cyclopentylsulfanyl]-acetyl}-mutilin in the form of ahydrochloride(mixture of cis-diastereoisomers) (DMSO-d₆): 8.4, 8.3(2xd,1H, NH, J=7.2Hz), 8.17(bs, 3H, NH₃ ⁺), 6.12, 5.06, 5.02(3xm, H₁₉, H₂₀,H₂₁), 5.55(d, 1H, H₁₄, J=8.3Hz), 4.53(bs, 1H, 11-OH), 4.15(m, 1H,H□-valyl), 3.2-3.5(m, H-1′, H-3′, H₁₁, H₂₂), 1.36, 1.35, 1.32, 1.05(4xs,9H, CH₃CS, (CH₃)₁₅, (CH₃)₁₈), 0.92, 0.91, 0.89, 0.88(2xd, 6H, (CH₃)₂CH,J=6.8Hz), 0.8, 0.62(2xd, (CH₃)₁₆, (CH₃)₁₇, J=6.8Hz)

Example 2014-O-[((3-(R/S)-Amino-cyclohexan-1-(R/S0-methyl-1-yl)sulfanyl)ace-tyl]mutilin in the form of a hydrochloride (d₆-DMSO): Rotamers: 7.90(b,3H, NH₃ ⁺), 6.15, 5.1(2xm, H₁₉, H₂₀, H₂₁), 5.52(d, 1H, J=5.2Hz, H₁₄),4.5(2xd, 1H, OH, J=6Hz), 3.4(t, 1H, H₁₁, J=6Hz), 3.3(m, 2H, H₂₂), 3.1(m,1H, NCH), 1.2, 1.25(2xs, 3H, CH₃CS)-1.18, 1.45(2xs, (CH3)₁₅, (CH3)₁₈),0.9(m, 6H, CH(CH₃)₂), 0.75, 0.88(2xd, (CH₃)₁₆, (CH₃)₁₇, J=5.4Hz)

Example 21a 14-O-[(3-(R*)-Guanidino-cyclohexan-1-(R*)-methyl-1-yl)-ace-tyl]mutilin in the form of a hydrochloride+14-O-[(3-(S*)-Guan-idino-cyclohexan-1-(S*)-methyl-1-yl)-acetyl]mutilin in the form of ahydrochloride (d₆-DMSO): 10.7, 8.6, 7.65, (3xm, 2H, NH), 6.7-7.5(b,2HNH), 6.15, 5.1(2xm, H₁₉, H₂₀, H₂₁), 5.52(d, 1H, J=5.2Hz, H₁₄), 5.5(d,1H, OH, J=6Hz), 3.9, 3.6(2x, m1H, CHNH), 3.4(t, 1H, H₁₁, J=6Hz), 3.3(m,2H, H₂₂), 1.4, 1.45(2xs, 3H, CH₃CS), 1.18, 1.45(2xs, (CH3)₁₅, (CH3)₁₈),0.75, 0.88(2xd, (CH₃)₁₆, (CH₃)₁₇, J=5.4Hz). Example 21b14-O-[(3-(R*)-Guanidino-cyclohexan-1-(S*)-meth- yl-1-yl)-acetyl]mutilinin the form of a hydrochloride+14-O-[(3-(S*)-Guanidino-cyclohexan-1-(R*)-methyl-1-yl)-ace- tyl]mutilinin the form of a hydrochloride (d₆-DMSO): 10.7, 8.6, 7.65, (3xm, 2H,NH), 6.7-7.5(b, 2HNH), 6.15, 5.1(2xm, H₁₉, H₂₀, H₂₁), 5.52(d, 1H,J=5.2Hz, H₁₄), 5.5(d, 1H, OH, J=6Hz), 3.9, 3.6(2x, m1H, CHNH), 3.4(t,1H, H₁₁, J=6Hz), 3.3(m, 2H, H₂₂), 1.4, 1.45(2xs, 3H, CH₃CS), 1.18,1.45(2xs, (CH3)₁₅, (CH3)₁₈), 0.75, 0.88(2xd, (CH₃)₁₆, (CH₃)₁₇, J=5.4Hz)

Example 22a14-O-[(3-(R*)-(R)-Valylamino-1-(R*)-methyl-1-yl)sulfanyl)-ace-tyl]mutilin and 14-O-[(3-(S*)-(R)-Valylamino-1-(S*)-methyl-1-yl)sul-fanyl)-acetyl]mutilin in the form of a hydrochloride (diastereoisomericmixture) (d₆-DMSO): 8.3(m, 1H, NHC═O), 8.1(b, 3H, NH₃ ⁺), 6.15, 5.1(2xm,H₁₉, H₂₀, H₂₁), 5.52(d, 1H, J=5.2Hz, H₁₄), 3.9(m, 1H, a-H-valyl),3.3-3.1(4xm, 4H, H₁₁, H₂₂, CHNH₃ ⁺), 4.5(b, 1H, OH), 1.25(b, 3H, CH₃CS),1.18, 1.45(2xs, (CH3)₁₅, (CH3)₁₈), 0.9(m, 6H, CH(CH₃)₂), 0.75, 0.88(2xd,(CH₃)₁₆, (CH₃)₁₇, J=5.4Hz) Example 22b14-O-[(3-(R*)-(R)-Valylamino-1-(S*)-methyl-1-yl)sulfanyl)-ace-tyl]mutilin and 14-O-[(3-S*)-(R)-Valylamino-1-(R*)-methyl-1-yl)sulfa-nyl)-acetyl]mutilin in the form of a hydrochloride (diastereoisomericmixture) (d₆-DMSO): 8.35(m, 1H, NHC═O), 8.1(b, 3H, NH₃ ⁺), 6.15,5.1(2xm, H₁₉, H₂₀, H₂₁), 5.52(d, 1H, J=5.2Hz, H₁₄), 3.95(m, 1H,a-H-valyl), 3.75(m, 1H, CHNH), 3.2-3.5(3xm, 3H, H₁₁, H₂₂,), 4.5(b, 1H,OH), 1.25(b, 3H, CH₃CS), 1.18, 1.45(2xs, (CH3)₁₅, (CH3)₁₈), 0.9(m, 6H,CH(CH₃)₂), 0.75, 0.88(2xd, (CH₃)₁₆, (CH₃)₁₇, J=5.4Hz)

Example 2314-O-[(3-(R/S)-Dimethylamino-methylenimino-cyclohexan-1-(R/S)-meth-yl-1-yl)-acetyl]mutilin in the form of a hydrochloride (d₆-DMSO): 9.2,8.1(2xb, 2H, NH), 6.15, 5.1(2xm, H₁₉, H₂₀, H₂₁), 5.52(d, 1H, J=5.2Hz,H₁₄), 4.5(d, 1H, OH, J=6Hz), 3.7(,m1H, CHNH), 3.4(t, 1H, H₁₁, J=6Hz),3.3(m, 2H, H₂₂), 3.1(b, 6H, N(CH₃)₂), 1.4, 1.45(2xs, 3H, CH₃CS), 1.18,1.45(2xs, (CH3)₁₅, (CH3)₁₈), 0.75, 0.88(2xd, (CH₃)₁₆, (CH₃)₁₇, J=5.4Hz)

-   -   14-O-(oximino-(C₃₋₈)cycloalkyl-sulfanylmethylcarbonyl)-pleuromutilins        and        14-O-(hydrazo-no-(C₃₋₈)cycloalkyl-sulfanylmethylcarbonyl)-pleuromutilins,        such as a compound of formula

wherein

-   R_(1B) has the meaning of R_(1A) as defined in formula I_(A),-   R_(2B) has the meaning of R_(2A) as defined in formula I_(A),-   R_(10B) has the meaning of R_(8A) as defined in formula I_(A),-   the dotted line has the meaning as defined in formula I_(A),-   m_(B) has the meaning of ma as defined in formula I_(A),-   R_(3B) Is hydrogen or (C₁₋₆)alkyl,-   X_(B) is —O—R_(4B) or —NR_(5B)R_(6B),-   R_(4B) is hydrogen or (C₁₋₆)alkyl, optionally substituted by a group    —NR_(7B)R_(8B),-   R_(6B) and R_(6B) independently of each other are (C₁₋₄)alkyl,-   R_(7B) and R_(8B) independently of each other are (C₁₋₄)alkyl, or-   R_(7B) and R_(8B) together with the nitrogen atom to which they are    attached form aliphatic heterocyclyl, having 5 to 8 ring members,    and-   R_(9B) is hydrogen or (C₁₋₄)alkyl;-   e.g. preferably R_(1B) has is hydrogen, R_(2B) has is hydrogen, the    dotted line is not present (single bond), m_(B) is 2, 3 or 4, R_(3B)    is hydrogen or (C₁₋₄)alkyl, such as methyl, X_(B) is as defined    above, R_(4B) is hydrogen or (C₁₋₄)alkyl, such as ethyl, substituted    by a group —NR_(7B)R_(8B), R_(5B) and R_(6B) are as defined above,    R_(7B) and R_(8B) independently of each other are (C₁₋₄)alkyl, e.g.    ethyl, or R_(7B) and R_(8B) together with the nitrogen atom to which    they are attached form pyrrolidine or piperidine, R_(9B) is as    defined above, and R_(10B) is hydrogen;-   e.g. including    14-O-(oximino-(C₃₋₈)cycloalkyl-sulfanylmethylcarbonyl)-pleuromutilins    and    14-O-(hydrazono-(C₃₋₈)cycloalkyl-sulfanylmethylcarbonyl)-pleuromutilins,    which are selected from the group consisting of compounds of formula    I_(EX) wherein R_(EX) is as set out in TABLE 3 (¹H-NMR-data of the    compounds described and obtained according, e.g. analogously, to a    process as described in the examples, are also indicated in TABLE    3):

TABLE 3

Example 24 14-O-{[(3-Hydroxyimino-cyclopentan-(R/S)-yl)-sulfanyl]-ace-tyl}-mutilin(syn and anti forms) Syn*-form: (DMSO-d₆): 10.33(s, 1H,═NOH), 6.15, 5.07, 5.03(3xm, H₁₉, H₂₀, H₂₁), 5.55(d, 1H, H₁₄, J=8.3Hz),4.5(d, 1H, 11-OH, J=6.1Hz), 3.25-3.45(m, SCH, H₁₁, H₂₂), 2.67(m, 1H,H-2a′), 1.35, 1.05(2xs, (CH₃)₁₅, (CH₃)₁₈), 0.8, 0.62(2xd, (CH₃)₁₆,(CH₃)₁₇, J=7Hz). Anti*-form: (DMSO-d₆): 10.36(s, 1H, ═NOH), 6.15, 5.07,5.02(3xm, H₁₉, H₂₀, H₂₁), 5.55(d, 1H, H₁₄, J=8.3Hz), 4.5(d, 1H, 11-OH,J=6.1Hz), 3.25-3.45(m, SCH, H₁₁, H₂₂), 2.74(m, 1H, H-2a′)1.35, 1.05(2xs,(CH₃)₁₅, (CH₃)₁₈), 0.8, 0.62(2xd, (CH₃)₁₆, (CH₃)₁₇, J=6.8Hz)

Example 25a14-O-{[(3-(E/Z)-Hydroxyimino-1-methyl-cyclopentan-(R*)-yl)-sul-fanyl]-acetyl}-mutilin ¹HNMR(DMSO-d₆): 10.33, 10.28(2xs, 1H, ═NOH),6.15, 5.07, 5.02(3xm, H₁₉, H₂₀, H₂₁), 5.55, 5.53(2xd, 1H, H₁₄, J=8.3Hz),4.5, 4.48(2xd, 1H, 11-OH, J=6.0Hz), 3.20-3.45(m, SCH, H₁₁, H₂₂), 1.35,1.05(3xs, CH₃CS, (CH₃)₁₅, (CH₃)₁₈), 0.8, 0.62(2xd, (CH₃)₁₆, (CH₃)₁₇,J=6.9Hz) Example 25b14-O-{[(3-(E/Z)-Hydroxyimino-1-methyl-cyclopentan-(S*)-yl)-sul-fanyl]-acetyl}-mutilin (DMSO-d₆): 10.32, 10.27(2xs, 1H, ═NOH), 6.15,5.07, 5.02(3xm, H₁₉, H₂₀, H₂₁), 5.55(d, 1H, H₁₄, J=8.3Hz), 4.5(d, 1H,11-OH, J=6.1Hz), 3.20-3.45(m, SCH, H₁₁, H₂₂), 1.35, 1.05(3xs, CH₃CS,(CH₃)₁₅, (CH₃)₁₆), 0.8, 0.62(2xd, (CH₃)₁₆, (CH₃)₁₇, J=6.8Hz)

Example 2614-O-{[(3-(2-Diethylamino-ethoxyimino)-cyclopentan-(R/S)-yl)-sul-fanyl]-acetyl}-mutilin in the form of a hydrochloride (syn/anti mixture)(DMSO-d₆): 9.9(bs, 1H, NH⁺), 6.15, 5.07, 5.03(3xm, H₁₉, H₂₀, H₂₁),5.55(d, 1H, H₁₄, J=8.1Hz), 4.3(m, 2H, OCH₂), 3.1-3.4(m, NCH₂, H₁₁, H₂₂),1.35, 1.05(2xs, (CH₃)₁₅, (CH₃)₁₈), 0.8, 0.62(2xd, (CH₃)₁₆, (CH₃)₁₇,J=6.8Hz)

Example 27a 14-O-[((E*-Hydroximino-cyclohexan-3-(R*)-yl)-sulfanyl)-ace-tyl]mutilin (d₆-DMSO): 10.31(s, 1H, HON═C), 6.15, 5.1(2xm, H₁₉, H₂₀,H₂₁), 5.52(d, 1H, J=5.2Hz, H₁₄), 4.55(d, 1H, OH, J=5Hz)3.4(t, 1H, H₁₁,J=5Hz), 3.3(m, 2H, H₂₂), 2.95(m, 1H, SCH), 2.78, 1.95(2xm, 2H, CH₂C═N),2.57, 2.09(2xm, 2H, CH₂═C═N), 1.18, 1.45(2xs, (CH3)₁₅, (CH3)₁₈), 0.75,0.88(2xd, (CH₃)₁₆, (CH₃)₁₇, J=5.4Hz). [α]_(D)=15.87°(c=1, MeOH) Example27b 14-O-[((E*-Hydroximino-cyclohexan-3-(S*)-yl)-sulfanyl)-ace-tyl]mutilin (d₆-DMSO): 10.31(s, 1H, HON═C), 6.15, 5.1(2xm, H₁₉, H₂₀,H₂₀, H₂₁), 5.52(d, 1H, J=5.2Hz, H₁₄), 4.50(d, 1H, OH, J=5Hz), 3.4(t, 1H,H₁₁, J=5Hz), 3.3(m, 2H, H₂₂), 2.95(m, 1H, SCH), 2.78, 1.95(2xm, 2H,CH₂C═N), 2.57, 2.09(2xm, 2H, CH₂═C═N), 1.18, 1.45(2xs, (CH3)₁₅,(CH3)₁₈), 0.75, 0.88(2xd, (CH₃)₁₆, (CH₃)₁₇, J=5.4Hz). [α]_(D)=38.5°(c=1,MeOH) Example 27c14-O-[((Z*-Hydroximino-cyclohexan-3-(R*)-yl)-sulfanyl)-ace- tyl]mutilin(d₆-DMSO): 10.31(s, 1H, HON═C), 6.15, 5.1(2xm, H₁₉, H₂₀, H₂₁), 5.52(d,1H, J=5.2Hz, H₁₄), 4.50(d, 1H, OH, J=5Hz), 3.45(t, 1H, H₁₁, J=5Hz),3.3(m, 2H, H₂₂), 2.90(m, 1H, SCH), 3.05, 2.05(2xm, 2H, CH₂C═N), 2.2(m,2H, CH₂═C═N), 1.18, 1.45(2xs, (CH3)₁₅, (CH3)₁₈), 0.75, 0.88(2xd,(CH₃)₁₆, (CH₃)₁₇, J=5.4Hz). [α]_(D)=13.62°(c=1, MeOH) Example 27d14-O-[((Z*-Hydroximino-cyclohexan-3-(S*)-yl)-sul- fanyl)acetyl]mutilin(d₆-DMSO): 10.31(s, 1H, HON═C), 6.15, 5.1(2xm, H₁₉, H₂₀, H₂₁), 5.52(d,1H, J=5.2Hz, H₁₄), 4.50(d, 1H, OH, J=5Hz), 3.45(t, 1H, H₁₁, J=5Hz),3.3(m, 2H, H₂₂), 2.90(m, 1H, SCH), 3.05, 2.05(2xm, 2H, CH₂C═N), 2.2(m,2H, CH₂═C═N), 1.18, 1.45(2xs, (CH3)₁₅, (CH3)₁₈), 0.75, 0.88(2xd,(CH₃)₁₆, (CH₃)₁₇, J=5.4Hz). [α]_(D)=42.83°(c=1, MeOH)

Example 28a 14-O-[((E-Hydroximino-cyclohexan-3-(R/S)-methyl-1-yl)-sul-fanyl)acetyl]mutilin (d₆-DMSO): 10.31(s, 1H, HON═C), 6.15, 5.1(2xm, H₁₉,H₂₀, H₂₁), 5.52(d, 1H, J=5.2Hz, H₁₄), 4.50(d, 1H, OH, J=5Hz), 3.45(t,1H, H₁₁, J=5Hz), 3.25(m, 2H, H₂₂), 1.25(s, 3H, CH₃, CH₃CS)1.18,1.45(2xs, (CH3)₁₅, (CH3)₁₈), 0.75, 0.88(2xd, (CH₃)₁₆, (CH₃)₁₇, J=5.4Hz)Example 28b 14-O-[((Z-Hydroximino-cyclohexan-3-(R/S)-methyl-1-yl)-sul-fanyl)acetyl]mutilin (d₆-DMSO): 10.31(s, 1H, HON═C), 6.15, 5.1(2xm, H₁₉,H₂₀, H₂₁), 5.52(d, 1H, J=5.2Hz, H₁₄), 4.50(d, 1H, OH, J=5Hz), 3.45(t,1H, H₁₁, J=5Hz), 3.25(m, 2H, H₂₂), 2.7(d, 1H, CHC═N, J=12Hz), 1.25(s,3H, CH₃, CH₃CS)1.18, 1.45(2xs, (CH3)₁₅, (CH3)₁₈), 0.75, 0.88(2xd,(CH₃)₁₆, (CH₃)₁₇, J=5.4Hz)

Example 2914-O-[((Z/E-Hydroximino-cyclohexan-3-(R/S)-methyl-5-(R/S)-meth-yl-1-yl)-sulfanyl)acetyl]mutilin (d₆-DMSO): Diastereoisomers: 10.2,10.28(3xs, 1H, HON═C), 6.15, 5.1(2xm, H₁₉, H₂₀, H₂₁), 5.52(d, 1H,J=5.2Hz, H₁₄), 4.50(d, 1H, OH, J=5Hz), 3.45(t, 1H, H₁₁, J=5Hz), 3.25(m,2H, H₂₂), 3.25, 1.7(2xm, 2H, CH₂C═N), 1.3, 1.34(2xs, 3H, CH₃, CH₃CS),1.18, 1.45(2xs, (CH3)₁₅, (CH3)₁₈), 0.75, 0.88(2xd, (CH₃)₁₆, (CH₃)₁₇,J=5.4Hz). MS-ESI: 534(M+1)

Example 3014-O-{[(3-(2-Diethylamino-ethoxyimino)-cyclohexan-(R/S)-yl)-sul-fanyl]-acetyl}-mutilin hydrochloride(E/Z mixture) (DMSO-d₆): 9.7(bs, 1H,NH⁺), 6.15, 5.07, 5.03(3xm, H₁₉, H₂₀, H₂₁), 5.55(d, 1H, H₁₄, J=8.0Hz),4.5, 4.25(2xm, 2H, OCH₂), 3.0-3.45(m, NCH₂, H₁₁, H₂₂), 1.35, 1.05(2xs,(CH₃)₁₅, (CH₃)₁₈), 0.8, 0.62(2xd, (CH₃)₁₆, (CH₃)₁₇, J=6.8Hz)

Example 31 14-O-[(((E/Z)-Dimethylaminimino-cyclohexan-3-(R/S)-1-yl)-sul-fanyl)acetyl]mutilin (d₆-DMSO): Diastereoisomers: 6.15, 5.1(2xm, H₁₉,H₂₀, H₂₁), 5.52(d, 1H, J=5.2Hz, H₁₄), 4.50(d, 1H, OH, J=5Hz), 3.45(t,1H, H₁₁, J=5Hz), 3.3(m, 2H, H₂₂), 3.2, 2.8(2xm, 1H, CHS), 2.95,1.85(2xm, 2H, CH₂C═N), 1.18, 1.45(2xs, (CH3)₁₅, (CH3)₁₈), 0.75,0.88(2xd, (CH₃)₁₆, (CH₃)₁₇, J=5.4Hz)

Example 32a14-O-[((E*-Hydroximino-cycloheptan-3-(R/S)-yl)-sulfanyl)-ace-tyl]mutilin NMR(d₆-DMSO): 10.35(s, 1H, HON═C), 6.15, 5.1(2xm, H₁₉, H₂₀,H₂₁), 5.52(d, 1H, J=5.2Hz, H₁₄), 4.5(d, 1H, OH, J=6.1Hz), 3.4(t, 1H,H₁₁, J=6.1Hz)), 3.3(m, 2H, H₂₂), 1.18, 1.45(2xs, (CH3)₁₅, (CH3)₁₈),0.75, 0.88(2xd, (CH₃)₁₆, (CH₃)₁₇, J=5.4Hz). Example 32b14-O-[((Z*-Hydroximino-cycloheptan-3-(R/S)-yl)-sul- fanyl)acetyl]mutilin(d₆-DMSO): 10.35(s, 1H, HON═C), 6.15, 5.1(2xm, H₁₉, H₂₀, H₂₁), 5.52(d,1H, J=5.2Hz, H₁₄), 4.5(d, 1H, OH, J=5Hz)3.4(t, 1H, H₁₁, J=5Hz), 3.3(m,2H, H₂₂), 3.05(m, 1H, SCH), 1.18, 1.45(2xs, (CH3)₁₅, (CH3)₁₈), 0.75,0.88(2xd, (CH₃)₁₆, (CH₃)₁₇, J=5.4Hz)

Example 3314-O-{[(3-(2-Diethylamino-ethoxyimino)-cyclohept-(R/S)-yl)-sul-fanyl]-acetyl}-mutilin hydrochloride(E/Z mixture) (DMSO-d₆): 9.85(bs,1H, NH⁺), 6.15, 5.06, 5.03(3xm, H₁₉, H₂₀, H₂₁), 5.55(d, 1H, H₁₄,J=8.5Hz), 4.52, 4.53(2xd, 1H, 11-OH, J=6.2Hz), 4.28(m, 2H, OCH₂),3.0-3.45(m, NCH₂, H₁₁, H₂₂), 1.35, 1.05 (2xs, (CH₃)₁₅, (CH₃)₁₈), 0.8,0.62(2xd, (CH₃)₁₆, (CH₃)₁₇, J=6.8Hz)

Example 3414-O-{[(3-(2-Pyrrolinine-1-yl-ethoxyimino)-cyclohept-1-(R/S)-yl)-sul-fanyl]-acetyl}-mutilin hydrochloride(E/Z mixture)- (DMSO-d₆): 10.2(bs,1H, NH⁺), 6.15, 5.08, 5.05(3xm, H₁₉, H₂₀, H₂₁), 5.58(d, 1H, H₁₄,J=8.3Hz), 4.53, 4.57(2xd, 1H, 11-OH, J=6.1Hz), 4.26(m, 2H, OCH₂),3.0-3.45(m, NCH₂, H₁₁, H₂₂), 1.38, 1.08(2xs, (CH₃)₁₅, (CH₃)₁₈), 0.83,0.64(2xd, (CH₃)₁₆, (CH₃)₁₇, J=6.8Hz).

Example 3514-O-{[(3-(2-Piperidine-1-yl-ethoxyimino)-cyclohept-(R/S)-yl)-sul-fanyl]-acetyl}-mutilin in the form of a hydrochloride(E/Z mixture)¹HNMR(DMSO-d₆): 10.0(bs, 1H, NH⁺), 6.15, 5.06, 5.03(3xm, H₁₉, H₂₀, H₂₁),5.55(d, 1H, H₁₄, J=8.4Hz), 4.5, 4.55(2xd, 1H, 11-OH, J=6.2Hz), 4.32(m,2H, OCH₂), 2.8-3.5(m, NCH₂, H₁₁, H₂₂), 1.35, 1.05(2xs, (CH₃)₁₅,(CH₃)₁₈), 0.8, 0.62(2xd, (CH₃)₁₆, (CH₃)₁₇, J=6.8Hz)

-   -   A compound of formula

wherein

-   R_(1C) has the meaning of R_(1A) as defined in formula I_(A).-   R_(2C) has the meaning of R_(2A) as defined in formula I_(A),-   the dotted line has the meaning as defined in formula I_(A),-   R_(4C) has the meaning of R_(6A) as defined in formula I_(A), and-   R_(3C) is amino, (C₁₋₄)alkylamino, di(C₁₋₄)alkylamino, the residue    of an amino acid, hydroxy, or (C₁₋₄)alkoxy,-   e.g. preferably R_(1C) is hydrogen, R_(2C) is hydrogen, R_(4C) is    hydrogen, the dotted line is not present (single bond), and R_(3C)    is amino, di(C₁₋₄)alkylamino, or the residue of an amino acid;-   e.g. including pleuromutilins which are selected from the group    consisting of compounds of formula I_(EX), wherein R_(EX) is as set    out in TABLE 4 (¹H-NMR-data of the compounds described and obtained    according, e.g. analogously, to a process as described in the    examples are also indicated in TABLE 4):

TABLE 4

Example 36a14-O-{[(3S,3aS,6S,6aR)-6-Amino-hexahydro-furo[3,2-b]furan-3-yl-sulfanyl]-acetyl}-mutilin in the form of a hydrochloride (DMSO-d₆):8.3(bs, 3H, NH₃ ⁺), 6.15, 5.05, 5.02(3xm, H₁₉, H₂₀, H₂₁), 5.55(d, 1H,8.2Hz, H₁₄), 4.65, 4.55(2xm, H₁₁-OH, H-3a′, H6a′), 3.6-4.1(m, 5H, H-2′,H-5′, H-6′), 3.3-3.5(m, 4H, H₁₁, H-3′, H₂₂), 1.35, 1.05(2xs, (CH₃)₁₅,(CH₃)₁₈), 0.8, 0.62(2xd, (CH₃)₁₆, (CH₃)₁₇, J=6.5Hz) Example 36b14-O-{[(3R,3aS,6S,6aR)-6-Amino-hexahydro-furo[3,2-b]furan-3-yl-sulfanyl]-acetyl}-mutilin-hydrochloride (DMSO-d₆): 8.3(bs, 3H, NH₃ ⁺),6.15, 5.07, 5.03(3xm, H₁₉, H₂₀, H₂₁), 5.55(d, 1H, H₁₄, J=8.2Hz), 4.60,4.7(2xm, H-3a′, H6a′), 3.6-4.1(m, 5H, H-2′, H-5′, H-6′), 3.3-3.5(m, 4H,H₁₁, H-3′, H₂₂), 1.35, 1.05, (2xs, (CH₃)₁₅, (CH₃)₁₈), 0.8, 0.62(2xd,(CH₃)₁₆, (CH₃)₁₇, J=6.9Hz) Example 36c14-O-{[(3S,3aS,6R,6aR)-6-Amino-hexahydro-furo[3,2-b]furan-3-yl-sulfanyl]-acetyl}-mutilin-hydrochloride (DMSO-d₆): 8.25(bs, 3H, NH₃ ⁺),6.15, 5.06, 5.03(3xm, H₁₉, H₂₀, H₂₁), 5.55(d, 1H, H₁₄, J=8.4Hz), 4.60(m,2H, H-3a′, H6a′), 3.55-4.2(m, 5H, H-2′, H-5′, H-6′), 3.35-3.5(m, 4H,H₁₁, H-3′, H₂₂), 1.35, 1.05(2xs, (CH₃)₁₅, (CH₃)₁₈), 0.8, 0.62(2xd,(CH₃)₁₆, (CH₃)₁₇, J=6.9Hz)

Example 3714-O-{[(3S,3aS,6S,6aR)-6-Dimethylamino-hexahydro-furo[3,2-b]fur-an-3-ylsulfanyl]-acetyl}-mutilin in the form of a hydrochloride(DMSO-d₆): 11.25(bs, 1H, NH⁺), 6.15, 5.06, 5.03(3xm, H₁₉, H₂₀, H₂₁),5.55(d, 1H, H₁₄, J=8.2Hz), 4.60(m, 1H, H3a′), 3.3-4.1(m, H-2′, H-5′,H-6′, H-6a′, H₁₁, H-3′, H₂₂), 2.8, 2.7(2xd, 6H, NH⁺(CH₃)₂, J=4.5Hz),1.35, 1.05(2xs, (CH₃)₁₅, (CH₃)₁₈), 0.8, 0.62(2xd, (CH₃)₁₆, (CH₃)₁₇,J=6.9Hz)

Example 38a14-O-{[(3S,3aS,6S,6aR)-6-((R)-Amino-3-methyl-butyrylamino)-hexa-hydro-furo[3,2-b]furan-3-ylsulfanyl]-acetyl}-mutilin in the form of ahydrochloride (DMSO-d₆): 8.65(d, 1H, NH, J=8.2Hz), 7.8(bs, 3H, NH₃ ⁺),6.15, 5.07, 5.02(3xm, H₁₉, H₂₀, H₂₁), 5.55(d, 1H, 5.2Hz, H₁₄), 4.55,4.45(2xm, 3H, H₁₁-OH, H-3a′, H6a′), 3.6-4.2(m, 5H, H-2′, H-5′, H-6′),3.4-3.5(m, 4H, H₁₁, H-3′, H₂₂), 1.35, 1.05(2xs, (CH₃)15, (CH₃)₁₈), 0.88,0.92(2xd, (CH₃)₂CH, J=6.8Hz), 0.8, 0.62(2xd, (CH₃)₁₆, (CH₃)₁₇, J=6.8Hz)Example 38b14-O-{[(3R,3aS,6S,6aR)-6-((R)-Amino-3-methyl-butyrylamino)-hexa-hydro-furo[3,2-b]furan-3-ylsulfanyl]-acetyl}-mutilin in the form of ahydrochloride (DMSO-d₆): 8.8(d, 1H, NH, J=7.1Hz), 8.15(bs, 3H, NH₃ ⁺),6.15, 5.07, 5.03(3xm, H₁₉, H₂₀, H₂₁), 5.55(d, 1H, 7.9Hz, H₁₄), 4.6,4.4(2xm, 2H, H-3a′, H6a′), 3.6-4.2(m, 5H, H-2′, H-5′, H-6′), 3.2-3.5(m,4H, H₁₁, H-3′, H₂₂), 1.35, 1.05(2xs, (CH₃)15, (CH₃)₁₈), 0.89, 0.91(d,(CH₃)₂CH, J=6.8Hz), 0.8, 0.62(2xd, (CH₃)₁₆, (CH₃)₁₇, J=6.8Hz) Example38c 14-O-{[(3S,3aS,6R,6aR)-6-((R)-Amino-3-methyl-butyrylamino)-hexa-hydro-furo[3,2-b]furan-3-ylsulfanyl]-acetyl}-mutilin in the form of ahydrochloride (DMSO-d₆): 8.4(d, 1H, NH, J=7.8Hz), 8.1(bs, 3H, NH₃ ⁺),6.15, 5.06, 5.02(3xm, H₁₉, H₂₀, H₂₁), 5.55(d, 1H, 8.2Hz, H₁₄), 4.6,4.5(2xm, 2H, H-3a′, H6a′), 3.6-4.4(m, 5H, H-2′, H-5′, H-6′), 3.3-3.5(m,4H, H₁₁, H-3′, H6a′), 3.6-4.4(m, 5H, H-2′, H-5′, H-6′), 3.3-3.5(m, 4H,H₁₁, H-3′, H₂₂), 1.35, 1.05(2xs, (CH₃)15, (CH₃)₁₈), 0.94, 0.90(d,(CH₃)₂CH, J=6.8Hz), 0.8, 0.62(2xd, (CH₃)₁₆, (CH₃)₁₇, J=6.8Hz)

Example 39a14-O-{[(3S,3aS,6R,6aR)-6-Hydroxy-hexahydro-furo[3,2-b]furan-3-yl-sulfanyl]-acetyl}-mutilin (DMSO-d₆): 6.15, 5.07, 5.03(3xm, H₁₉, H₂₀,H₂₁), 5.55(d, 1H, H₁₄, J=8.3Hz), 4.85(d, 1H, 6′-OH, J=6.4Hz), 4.5(d, 1H,11-OH, J=6.1Hz), 3.65-4.45(m, H-3a′, H-6a′, H-2′, H-5′, H-6′),3.3-3.45(m, H-5′, H₁₁, H-3′, H₂₂), 1.35, 1.05(2xs, (CH₃)₁₅, (CH₃)₁₈),0.8, 0.62(2xd, (CH₃)₁₆, (CH₃)₁₇, J=6.9Hz) Example 39b14-O-{[(3R,3aS,6R,6aR)-6-Hydroxy-hexahydro-furo[3,2-b]furan-3-yl-sulfanyl]-acetyl}-mutilin (DMSO-d₆): 6.15, 5.06, 5.03(3xm, H₁₉, H₂₀,H₂₁), 5.55(d, 1H, H₁₄, J=8.3Hz), 4.8(d, 1H, 6′-OH, J=5.7Hz), 4.5(d, 1H,11-OH, J=6.1Hz), 3.7-4.45(m, H-3a′, H-6a′, H-2′, H-5′, H-6′), 3.2-3.5(m,H-5′, H₁₁, H-3′, H₂₂), 1.35, 1.05(2xs, (CH₃)₁₅, (CH₃)₁₈), 0.8, 0.62(2xd,(CH₃)₁₆, (CH₃)₁₇, J=6.8Hz) Example 39c14-O-{[(3S,3aS,6S,6aR)-6-Hydroxy-hexahydro-furo[3,2-b]furan-3-yl-sulfanyl]-acetyl}-mutilin (DMSO-d₆): 6.1, 5.07, 5.02(3xm, H₁₉, H₂₀,H₂₁), 5.55(d, 1H, H₁₄, J=8.3Hz), 5.2(d, 1H, 6′-OH), 3.55-4.55(m, 11-OH,H-3a′, H-6a′, H-2′, H-5′, H-6′), 3.3-3.45(m, H₁₁, H-3′, H₂₂), 1.35,1.05(2xs, (CH₃)₁₅, (CH₃)₁₈), 0.8, 0.62(2xd, (CH₃)₁₆, (CH₃)₁₇, J=6.8Hz)

-   -   14-O-(hydroxy- or        oxo)-(heterocyclyl-sulfanylmethylcarbonyl)-pleuromutilins,        wherein heterocyclyl is an aliphatic ring of 4 to 8 ring        members, preferably 5 to 7, comprising one nitrogen as the        heteroarom, e.g. a compound of formula

wherein

-   R_(1D) has the meaning of R_(1A) as defined above,-   R_(2D) has the meaning of R_(2A) as defined above,-   R_(4D) has the meaning of R_(6A) as defined above,-   the dotted line has the meaning as defined above, and-   R_(3D) is aliphatic heterocyclyl of 4 to 8 ring members, and    comprising one nitrogen atom as the heteroatom, or (C₄₋₈)cycloalkyl,    which heterocyclyl or cycloalkyl is substituted by hydroxy or oxo;-   e.g. preferably R_(1D) is hydrogen or deuterium, R_(2D) is hydrogen    or deuterium, the dotted line is not present (single bond), R_(3D)    is as defined above, e.g. heterocyclyl has preferably 5 to 7 ring    members, e.g. heterocyclyl is attached to the sulphur in a compound    of formula ID via a carbon bond; such as hydroxypyrrolidino,    hydroxypiperidino, oxo-perhydroazepinyl; and-   cycloalkyl is preferably (C₅₋₆)cycloalkyl, e.g. cyclopentanonyl,    R_(4D) is hydrogen or deuterium, e.g. including 14-O-(hydroxy- or    oxo-hetrocyclyl-sulfanylmethylcarbonyl)-pleuromutilins, wherein    heterocyclyl is an aliphatic ring of 4 to 8 ring members, preferably    5 to 7, comprising one nitrogen as the heteroarom, which are    selected from the group consisting of pleuromutilins which are    selected from the group consisting of compounds of formulae

-    wherein R_(EX) is as set out in TABLE 5 (the compounds of TABLE 5    are compounds of formula I_(EX), with the exception of the compound    of Example 41 which is a compound of formula I″_(EX); ¹H-NMR-data of    the compounds described and obtained according, e.g. analogously, to    a process as described in the examples are also indicated in TABLE    5):

TABLE 5

Example 4014-O-[(3-R*-Hydroxypyrrolidine-4-(R*)yl)-sulfanyl-acetyl]-mutilin and14-O-[(3-S*-Hydroxypyrrolidine-4-(S*)yl)-sulfanyl-acetyl]-mu- tilin inthe form of a hydrochloride(diastereoisomeric mixture) (d-6-DMSO): 9.4,9.65(2xb, 2H, NH₂ ⁺), 3.6, 3.2(2xm, 4H, CH₂NCH₂), 4.45(m, 1H, CHO),3.45-3.32(m, 3H, H₁₁H₂₂), 3.95(m, 1H, CHS), 1.18, 1.45(2xs, (CH3)₁₅,(CH3)₁₈), 0.75, 0.88(2xd, (CH₃)₁₆, (CH₃)₁₇, J=5.4Hz 0.98)

Example 412,2,4-Trideutero-14-O-[((3-(S*)-hydroxy-piperidine-4-(S*)-yl)sul-fanyl)-acetyl]mutilin in the form of a deuterochloride (d-6-DMSO, 350K):8.05(b, 3H, NH₃ ⁺), 4.25-4.1(m, 3H, CH₂N, NHCHC═O), 3.75(m, 1H, CHO),3.45-3.32(m, 3H, H₁₁H₂₂), 2.89(m, 1H, CHS), 1.18, 1.45(2xs, (CH3)₁₅,(CH3)₁₈), 0.9(m, 6H, CH(CH₃)₂), 0.75, 0.88(2xd, (CH₃)₁₆, (CH₃)₁₇,J=5.4Hz 0.98). The signals of the 2,2′- and 4-protons of the tricyclicmoiety are missing in thast spectrum. Mass Spectroscopy(MS): m/e: 496

Example 42 14-O-[(3R*-Hydroxypiperidin-4-(R*)yl)-sulfanyl-acetyl]mutilinin the form of ahydrochloride+14-O-[(3S*-Hydroxypiperidin-4-(S*)yl)-sul-fanyl-acetyl]mutilin in the form of a hydrochloride (d-6-DMSO, 350K):8.05(b, 3H, NH₃ ⁺), 4.25-4.1(m, 3H, CH₂N, NHCHC═O), 3.75(m, 1H, CHO),3.45-3.32(m, 3H, H₁₁H₂₂), 2.89(m, 1H, CHS), 1.18, 1.45(2xs, (CH3)₁₅,(CH3)₁₈), 0.9(m,6H, CH(CH₃)₂), 0.75, 0.88(2xd, (CH₃)₁₆, (CH₃)₁₇, J=5.4Hz0.98)

Example 43 14-O-[((Azepan-2-one-4-(R/S)-yl)-sulfanyl acetyl)]-mutilin(d₆-DMSO): 6.15, 5.1(2xm, H₁₉, H₂₀, H₂₁), 5.52(d, 1H, J=5.2Hz, H₁₄),3.4(m, 1H, H₁₁,), 3.3(m, 2H, H₂₂), 3.1(m, 2H, SCH, CHN), 1.18, 1.45(2xs,(CH3)₁₅, (CH3)₁₈), 0.75, 0.88(2xd, (CH₃)₁₆, (CH₃)₁₇, J=5.4Hz)

Example 44 14-O-{[(3-Oxo-cyclopentan-(R/S)-yl)-sulfanyl]-acetyl}-mutilin(CDCl₃): 6.45, 5.35, 5.2(3xm, H₁₉, H₂₀, H₂₁), 5.8(d, 1H, H₁₄, J=8.4Hz),3.6(m, 1H, SCH), 3.35(m, 1H, 11-OH), AB-system(ν_(A)=3.25, ν_(B)=3.17,2H, H₂₂, J=14.8Hz), 2.65(m, ½H, H-2a′), 2.6(m, ½H, H-2a′), 1.45,1.18(2xs, (CH₃)₁₅, (CH₃)₁₈), 0.9, 0.75(2xd, (CH₃)₁₆, (CH₃)₁₇, J=6.8Hz)

Compounds provided by the present invention, the formulae of which areas set out in TABLE 1 to TABLE 5, and compounds of formulae I_(A),I_(B), I_(C), I_(D), I_(EX), I′_(EX) and I″_(EX) are herein designatedas “SPECIAL compound(s) of (according to) the present invention”. “Theresidue of an amino acid”, whenever defined in any one of the SPECIALcompounds of the present invention includes that part of an amino acid,e.g. including natural and synthetic amino acids, e.g. valine and otheramino acids as defined herein, most preferably valine; which remains ifthe hydroxy group from the carboxylic acid group is splitt off, e.g. Incase of valine [HO—CO—CH(NH₂)—CH(CH₃)₂] the residue—CO—CH(NH₂)—CH(CH₃)₂.

In a SPECIAL compound of the present invention each single definedsubstitutent may be a preferred substituent, e.g. independently of eachother substitutent defined. A SPECIAL compound of the present inventionincludes a compound in any form, e.g. in free form, in the form of asalt, in the form of a solvate and in the form of a salt and a solvate.

A salt of a SPECIAL compound of the present invention includes apharmaceutically acceptable salt, e.g. including a metal salt or an acidaddition salt. Metal salts include for example alkali or earth alkalisalts; acid addition salts include salts of a compound of formula I withan acid, e.g. hydrogen fumaric acid, fumaric acid,naphthalin-1,5-sulphonic acid, phosphoric acid, tartaric acid, citricacid, hydrochloric acid, deuterochloric acid; preferably hydrochloricacid. A SPECIAL compound of the present invention in free form may beconverted into a corresponding compound in the form of a salt; and viceversa. A SPECIAL compound of the present invention in free form or inthe form of a salt and in the form of a solvate may be converted into acorresponding compound in free form or in the form of a salt inunsolvated form; and vice versa. A SPECIAL compound of the presentinvention may exist in the form of isomers and mixtures thereof; e.g.optical isomers, diastereoisomers, cis-, trans-conformers. A SPECIALcompound of the present invention may e.g. contain asymmetric carbonatoms and may thus exist in the form of diastereoisomeres and mixturesthereof, e.g. racemates. For example a SPECIAL compound of the presentinvention may comprise the residue of an amino acid. In such amino acidresidue the carbon atom to which the amino group is attached may be anasymmetric carbon atom and the amino group attached may thus be in theR— or S-configuration. A SPECIAL compound of the present invention maycomprise a cycloalkyl, e.g. attached to the sulfanyl group, whichcycloalkyl may be further substituted, and said substitutents may existin the cis or in the trans conformation. E.g., the carbon atom of acycloalkyl group to which the sulfanylgroup is attached may beasymmetric, e.g. if said cycloalkyl is further substituted, andsubstitutents attached to said cycloalkyl group may be in the R— or inthe S-configuration. E.g., a SPECIAL compound of the present inventionalso may comprise an oxime group. The hydroxgroup attached to the iminogroup may be in syn- or in anti-configuration. Isomeric mixtures may beseparated as appropriate, e.g. according, e.g. analogously, to a methodas conventional, to obtain pure isomers. The present invention includesa SPECIAL compound of the present invention In any isomeric form and inany isomeric mixture.

The present invention also includes tautomers of a SPECIAL compound ofthe present invention where such tautomers can exist.

Any compound described herein, e.g. a SPECIAL compound of the presentinvention, may be prepared as appropriate, e.g. according to a method asconventional, e.g. analogously, e.g. or as specified herein.

A SPECIAL compound of the present invention, e.g. a compound of formula

wherein

-   R_(1P) has the meaning of R_(1A) as defined above,-   R_(2P) has the meaning of R_(2A) as defined above,-   R_(3P) has the meaning of R_(6A) as defined above,-   the dotted line has the meaning as defined above, and-   R_(P) has the meaning as set out in any one of the compounds of    TABLE 1 to TABLE 5, and in a compound of formulae I_(A), I_(B),    I_(C), I_(D), I_(EX), I′_(EX) and I″_(EX),-   may be prepared as appropriate, e.g. including a process comprising    the steps of-   a. reacting a compound of formula

-   wherein R_(1P) and R_(2P) are as defined above, and the dotted line    has the meaning as defined above,-   with thiourea and subsequent reduction to obtain a compound of    formula

wherein R_(1P) and R_(2P) are as defined above,

-   b. reacting a compound of formula II_(P) obtained in step a, with a    compound of formula    R_(p)—H

wherein R_(P) is as defined above, in a reactive form, e.g. a mesylateor a tosylate, optionally in a protected form,

to obtain a compound of formula I_(P) (i.e. a SPECIAL compound of thepresent invention), or to obtain a pre-form of a compound of formulaI_(P),

-   c. optionally further reacting a pre-form obtained in step b. to    obtain a compound of formula I_(P), e.g. introducing deuterium to    obtain a compound of formula I_(P) wherein the subsitutents are as    defined above, and-   d. isolating a compound of formula I_(P) obtained in step b. or in    step c. from the reaction mixture.

R_(P) is substituted (C₄₋₈)cycloalkyl, substituted phenyl, substitutedaliphatic heterocyclyl, having 4 to 8 ring members and comprising as aheteroatom 1 or 2 nitrogen atoms, alkyl, substituted by (substituted)amino, alkyl substituted by heterocyclyl, or substituted, bicyclicaliphatic heterocyclyl, comprising in each ring 5 ring members and oneoxygen heteroatom, e.g. including the meanings of R_(P) in the SPECIALpleuromutilins of the present invention, e.g. such as set out in any oneof the compounds of TABLE 1 to TABLE 5, and in a compound of formulaeI_(A), I_(B), I_(C), I_(D), I_(EX), I′_(EX) and I″_(EX).

A process for the production of the SPECIAL compounds of the presentinvention may e.g. be carried out analogously to processes as set out inany of the patent references cited herein, e.g. analogously to a processfor the production of compounds as described in patent literature citedherein, such as in WO0109095, WO0204414 and WO0222580, or as describedherein. All patent references cited herein are introduced by reference,especially with respect to the claim scopes and meanings of thesubstituents, e.g. including the preferred meanings of thesubstitutents, and with respect to production processes.

A pleuromutilin of the present invention includes the SPECIAL compoundsof the present invention of formula I_(P). A pleuromutilin of thepresent invention includes one or more, preferably one, pleuromutilinsof the present invention, e.g. one pleuromutilin or a combination ofdifferent pleuromutilins of the present invention.

We have found that SPECIAL compounds of the present invention, includingcompounds of formula I_(P), exhibit pharmacological activity similar topleuromutilins in similar indications, e.g. as described in WO0109095,WO0204414 and WO0222580, e.g. in test systems similar as described inWO0109095, WO0204414 and WO0222580, and expectedly additionally in testsystems as described herein. Compounds of formula I_(P) are thereforeuseful as pharmaceuticals.

For pharmaceutical treatment, the appropriate dosage of a pleuromutilinwill, of course, vary depending upon, for example, the chemical natureand the pharmakokinetic data of a pleuromutilin of the present inventionused, the individual host, the mode of administration and the nature andseverity of the conditions being treated. However, in general, forsatisfactory results in larger mammals, for example humans, an indicateddaily dosage is in the range from about 0.05 g to about 5.0 g, of apleuromutilin of the present invention; conveniently administered, forexample, in divided doses up to four times a day.

A pleuromutilin of the present invention may be administered by anyconventional route, for example enterally, e.g. including nasal, buccal,rectal, oral administration; parenterally, e.g. including intravenous,intramuscular, subcutanous administration; or topically; e.g. includingepicutaneous, intranasal, intratracheal administration;

-   e.g. in form of coated or uncoated tablets, capsules, injectable    solutions or suspensions, e.g. in the form of ampoules, vials, in    the form of creams, gels, pastes, inhaler powder, foams, tinctures,    lip sticks, drops, sprays, or in the form of suppositories.

Pleuromutilins of the present invention may be administered in the formof a pharmaceutically acceptable salt, e.g. an acid addition salt ormetal salt; or in free form; optionally in the form of a solvate.Pleuromutilins of the present invention in the form of a salt exhibitthe same order of activity as the pleuromutilins of the presentinvention in free form; optionally in the form of a solvate.

A pleuromutilin of the present invention may be used for pharmaceuticaltreatment according to the present invention alone, or in combinationwith one or more other pharmaceutically active agents, e.g. such whichshow pharmaceutical activity against H.pylori infections, e.g. includingantimicrobials, such as tetracycline, amoxicillin, metronidazole,clarithromycin, and mixtures of proton-pump inhibitors, such asomeprazole or lansoprazole, together with a second antimicrobial, e.g.amoxicillin or clarithromycin.

In another aspect the present invention provides the use of apleuromutilin in combination with one or more other pharmaceuticallyactive agents in the preparation of a medicament for the treatment ofdiseases mediated by Helicobacter pylori.

In another aspect the present invention provides a method for thetreatment of diseases mediated by Helicobacter pylori, comprisingadministering to a subject in need of such treatment an effective amountof a pleuromutilin in combination with one or more otherpharmaceutically active agents.

Combinations include fixed combinations, in which two or morepharmaceutically active agents are in the same formulation; kits, inwhich two or more pharmaceutically active agents in separateformulations are sold in the same package, e.g. with instruction forco-administration; and free combinations in which the pharmaceuticallyactive agents are packaged separately, but instruction for simultaneousor sequential administration are given.

A pharmaceutical composition comprising a pleuromutilin of the presentinvention further comprises at least one pharmaceutical excipient, e.g.appropriate carrier and/or diluent, e.g. including fillers, binders,disintegrators, flow conditioners, lubricants, sugars and sweeteners,fragrances, preservatives, stabilizers, wetting agents and/oremulsifiers, solubilizers, salts for regulating osmotic pressure and/orbuffers.

Such compositions may be manufactured according, e.g. analogously to amethod as conventional, e.g. by mixing, granulating, coating, dissolvingor lyophilizing processes. Unit dosage forms may comprise, for example,from about 0.5 mg to about 1500 mg, such as 1 mg to about 500 mg.

Pleuromutilins of the present invention for administration in diseasesmediated by H.pylori, may be administered in a similar mode and insimilar dosages as other active agents in H.pylori treatment, such asamoxicillin or clarithromycin.

A pleuromutilin of the present invention is preferably selected from acompound of formula I-Valnemulin (Econor®) or a compound of formulaI_(S)-WO0109095, e.g. a compound of formula

-   e.g. in free form or in the form of a pharmaceutically acceptable    salt.

Activity against strains of Helicobacter pylori is determined accordingto the Agar Dilution Method, using Mueller Hinton agar, supplementetwith >2 week old horse blood (5% v/v), incubation at 35° C. for 3 daysin a gas system-generated microaerobic atmosphere according to NCCLSrecommendations, such as disclosed e.g. in “Methods for dilutionantimicrobial susceptibility tests for bacteria that grow aerobically”—Fourth edition; approved standard. M7-A4 Vol. 17 No. 2 (1997) andM100-S9 Vol. 19 No. 1 (1999).

Pleuromutilins of the present invention show activity in such TestMethods against strains of H.pylori and are thus useful in the treatmentof infections mediated, e.g. caused, by H.pylori. Pleuromutilins of thepresent invention surprisingly may be even active against resistantH.pylori strains, e.g. strains which are resistant against treatmentwith known pharmaceuticals useful in the treatment of diseases caused byH.pylori infections, e.g. metronidazole resistant strains.

In the following Examples all temperatures are in degree Centigrade andare uncorrected. The following abbreviations are used:

BOC: tert.butoxyxcarbonyl DCC: dicyclohexylcarbodiimide DMF:N,N-dimethylformamide DMSO: dimethylsulfoxide EDC:N-(3-dimethylaminopropyl)-N′- EtOH: ethanol ethylcarbodiimidehydrochloride MeOH: methanol EtAc: ethyl acetate RT: room temperatureHOBT: 1-hydroxybenzotriazole TFA: trifluoroacetic acid MS: massspectroscopy TBAF: tetra-n-butylammonium fluoride THF: tetrahydrofurane

Chromatography is carried out on silica gel.

PREPARATION EXAMPLES I. Preparation of (SPECIAL) Pleuromutilins of thePresent Invention Example I-A14-O—[(N-(3-Methyl-2(R)-amino-butyryl)piperidine-3-yl)-sulfanylacetyl]-mutilinin the form of a hydrochloride I-AA)14-O—[(N—BOC-Piperidin-3(S)-yl)-sulfanylacetyl]-mutilin

Method 1:

532 mg of 22-O-tosyl-pleuromutilin are added to a solution of 217 mg ofN—BOC-piperidine-3(S)-thiol and 112 mg potassium tert. butylate in 10 mlof THF, the mixture obtained is stirred for 3 hours, the mixtureobtained is distributed between EtAc and brine, the organic phaseobtained is dried, solvent is evaporated and the evaporation residueobtained is subjected to chromatography.14-O—[(N—BOC-Piperidin-3(S)-yl)-sulfanylacetyl]-mutilin is obtained.

Method 2:

A solution of 1.97 g of 22-mercapto-pleuromutilin, 1.39 g ofN—BOC-3(R)-methylsulfonyloxy-piperidine and 0.12 g of sodium in 50 ml ofEtOH is heated to 90° for 12 hours, from the mixture obtained solvent isevaporated and the evaporation residue is subjected to chromatography.14-O—[(N—BOC-piperidin-3-yl)-sulfanylacetyl]-mutilin is obtained.

¹H-MR(CDCl₃):6.45,5.35,5,2(3×m,H₁₉,H₂₀,H₂₁),5.74(d,1H,5.2Hz,H₁₄),3.35(d,1H,H₁₁,J=5.2 Hz), AB-system: 3.12,3.18, J=14.7 Hz,H₂₂),3.2,2.95,2.65,2.6(4×m,CH₂NCH₂), 2.85 (m,1H, SCH),1.18,1.45(2×s,(CH3)₁₅,(CH3)₁₈), 0.75,0.88(2×d,(CH₃)₁₆, (CH₃)₁₇,J=5.4 Hz)

I-AB)14-O—[(N-(3-Methyl-2(R)-amino-butyryl)-piperidine-3-yl)-sulfanylacetyl]-mutilinin the form of a hydrochloride

A solution of 280 mg of14-O—[(N—BOC-piperidin-3-yl)-sulfanylacetyl]-mutilin in 20 ml of CH₂Cl₂and 1 ml of TFA is stirred at RT for 30 minutes and from the mixtureobtained solvent is evaporated. The evaporation residue obtained istreated with 40 ml of CH₂Cl₂, 55 mg of N-methyl-morpholine, 110 mg ofN—BOC—(R)-valine and 105 mg of DCC are added and the mixture obtained isstirred for 3 hours. From the mixture obtained precipitateddicyclohexylurea is filtered off and the filtrate obtained is subjectedto chromatography. Purified14-O—[(N-(3-Methyl-2(R)-amino-butyryl)-piperidine-3-yl)-sulfanylacetyl]-mutilinobtained is treated with TFA in CH₂Cl₂, solvent is evaporated and theevaporation residue obtained is treated with etheric HCl.14-O—[(N-(3-Methyl-2(R)-amino-butyryl)-piperidine-3-yl)-sulfanylacetyl]-mutilinin the form of a hydrochloride is obtained.

¹H-NMR(d-6-DMSO,330K): 6.45,5.35,5,2(3×m,H₁₉,H₂₀,H₂₁), 5.74 (d,1H,5.2Hz,H₁₄), 5.45 (d,1H,NH,J=7.8 Hz), 4.1 (m,1H,NHCHCO), 3.35(d,1H,H₁₁,J=5.2 Hz), AB-system: 3.12,3.18, J=14.7 Hz,H₂₂), 3.2, 2.95,2.65 ,2.6 (4×m,CH₂NCH₂), 2.8 (m,1H,SCH), 1.18,1.45(2×s,(CH3)₁₅,(CH3)₁₈), 0.75,0.88 (2×d,(CH₃)₁₆,(CH₃)₁₇,J=5.4 Hz),0.78.0.84 (2×d, (CH₃)₂CHJ=6.8 Hz)

Example I-B14-O—[(N-(3Methyl-2(R)-amino-butyryl)-piperidine-3(S)-yl)-sulfanylacetyl]-2(S)-fluoro-mutilinin the form of a hydrochloride IBA)14-O-(Tosyloxyacetyl)-2(S)-fluoro-mutilin

To a solution of 500 mg of 14-O-(hydroxyacetyl)-2(S)-fluoro-mutilin (seee.g. Vyplel H., et al J Fluorine Chem; 23, 482 (1983)), in 5 ml ofCH₂Cl₂ 450 mg of toluene sulfonic acid anhydride and 0.21 ml of pyridineare added and the mixture obtained is stirred for 4 hours at RT. Themixture obtained is diluted with CH₂Cl₂ and extracted with 1N HCl,aqueous NaHCO₃ and H₂O. The organic phase obtained is dried, solvent isevaporated and the evaporation residue is subjected to chromatography.14-O-[tosyloxyacetyl]-2(S)-fluoro-mutilin is obtained.

IBB)14-O—[(N-(3-Methyl-2(R)-amino-butyryl)-piperidine-3(S)-yl)-sulfanylacetyl]-2(S)-fluoro-mutilinin the form of a hydrochloride

is obtained starting from 14-O-[tosyloxyacetyl]-2(S)-fluoro-mutilinanalogously to the method of Example IAB). Characterisation data seeTABLE 1, Example 12.

Example I-C 14-O-[(3-Guanidino-phenylsulfanyl)-acetyl]mutilin in theform of a hydrochloride ICA)14-O-[(3-Amino-phenylsulfanyl)-acetyl]-mutilin

A solution of 0.92 g of sodium and 5 g of 3-amino-thiophenol in 100 mlof dry EtOH is added to a solution of 21.3 g of 22-O-tosyl-pleuromutilin(see e.g. H.Egger et al., J.Antibiotics 29, 923 (1976)) in 250 ml ofethylmethylketone at 25° under careful temperature control. The mixtureobtained is kept for 15 hours at 25°, filtered and the filtrate obtainedis concentrated under reduced pressure and subjected to chromatography.14-O-[(3-Amino-phenylsulfanyl)-acetyl]-mutilin is obtained.¹H-NMR(CDCl₃): 0.58(d, 3H, H₁₆, J=7.2 Hz), 0.81 (d, 3H, H₁₇, J=7.3Hz),1.02 (s, 3H, H₁₈), 1.32 (s, 3H, H₁₅), ABX-system(ν_(A)=1.2,ν_(B)=1.88, H_(13a), H_(13b), J=16.1 Hz, J=9.1 Hz), 2.08(d,1H, H₄, J=2.1Hz), ABXY-system(ν_(A)=2.23, V_(B)=2.19, H_(2a), H_(2b), J=16.2 Hz,J=9.1 Hz, J=1.8 Hz), 2.3(m,1H,H₁₀), 3.4 (d,1H,H₁₁, J=5.98 Hz), AB-system(ν_(A)=3.81, ν_(B)=3.89, 2H, H₂₂, J=14.1 Hz), 5.18(dd,1H, H_(20a),J=17.5 Hz, J=1.6 Hz), 5.29(dd,1H, H_(20b), J=11 Hz, J=1.6 Hz),5.51(d,1H, H₁₄, J=8.3 Hz), 6.05 (dd,1H,H₁₉, J=11 Hz, J=17.5 Hz), 7.0 (m,1H,arom.H), 7.18 (m2H, arom.H), 7.3 t,1H, arom.H₅, J=8 Hz).

ICB) 14-O-[(3-Guanidino-phenylsulfanyl)-acetyl]mutilin in the form of ahydrochloride

A solution of 2.4 g of 14-O-[(3-amino-phenylsulfanyl)-acetyl]mutilin,1.5 g of cyanamide and 0.44 ml of HCl conc. in 20 ml of dioxane isstirred at room temperature for 28 hours.14-O-[(3-Guanidino-phenylsulfanyl)-acetyl]mutilin in the form of ahydrochloride in crystalline form is obtained. Characterisation data seein TABLES above.

Exmple I-D 14-O-[(3R*-Hydroxypiperidin-4-(R*)yl)-sulfanyl-acetyl]mutilinand 14-O-[(3S*-Hydroxypiperidin-4-(S*)yl)-sulfanyl-acetyl]mutilin in theform of a hydrochloride (diastereoisomeric mixture)

1.06 g of pleuromutilin-22-O-tosylate dissolved in 1 ml of 2-butanoneare slowly added to a solution of 466 mg ofN—BOC-3-hydroxy-piperidin-4-thiol and 224 mg of potassium-tert. butylatein 20 ml of THF, the mixture obtained is stirred for 2 hours, themixture obtained is distributed between brine and EtAc, extracted with0.1N HCl, and the phases obtained are separated. The organic phaseobtained is dried, and the evaporation residue obtained is subjected tochromatography. A mixture of14-O-[(3R*-Hydroxypiperidin-4-(R*)yl)-sulfanyl-acetyl]mutilin and14-O-[(3S*-Hydroxypiperidin-4-(S*)yl)-sulfanyl-acetyl]mutilin isobtained which is treated with etheric HCl to obtain the correspondinghydrochloride. Characterisation data see in TABLE 5, Example 42.

Example I-E2,2,4-Trideutero-14-O-[((3-(S*)-hydroxy-piperidine-4-(S*)-yl)sulfanyl)-acetyl]mutilinin the form of a deuterochloride

A solution of 300 mg of the compound obtained in Example ID in 30 mldioxane with 5 ml of DCl (20% in D₂O) is kept for 6 days at 25°. Fromthe mixture obtained solvent is evaporated and the concentration residueis subjected to lyophilization.2,2,4-Trideutero-14-O-[((3-(S*)-hydroxy-piperidine-4-(S*)-yl)sulfanyl)-acetyl]mutilinin the form of a deuterochloride is obtained. Characterisation data seeTABLE 5, Example 41.

Example I-F

-   14-O-[3-(R*)-((N—BOC—(R)-Valyl-amino-cyclohexan-1-(R*)-yl)sulfanyl)-acetyl]mutilin    (a)-   14-O-[3-(S*)-((N—BOC—(R)-Valyl-amino-cyclohexan-1-(S*)-yl)sulfanyl)-acetyl]mutilin    (b)-   14-O-[3-(S*)-((N—BOC—(R)-Valyl-amino-cyclohexan-1-(R*)-yl)sulfanyl)-acetyl]mutilin    (c)-   14-O-[3-(R*)-((N—BOC—(R)-Valyl-amino-cyclohexan-1-(S*)-yl)sulfanyl)-acetyl]mutilin    (d)

2.66 g of pleuromutilin-22-O-tosylate dissolved in 10 ml THF are slowlyadded to a solution of 1.65 g of3-(N—BOC—(R)-valyl-amino)-cyclohexane-(R/S)-thiol and 560 mg ofpotassium-tert. butylate in 25 ml of THF, the mixture obtained isstirred for 2 hours and distributed between brine and EtAc. The mixtureobtained is extracted with 0.1N HCl , the organic phase obtained isdried, solvent is evaporated and the evaporation residue obtained issubjected to chromatography. Pure

-   (a)    14-O-[3-(R*)-((N—BOC—(R)-Valyl-amino-cyclohexan-1-(R*)-yl)sulfanyl)-acetyl]mutilin-   (b)    14-O-[3-(S*)-((N—BOC—(R)-Valyl-amino-cyclohexan-1-(S*)-yl)sulfanyl)-acetyl]mutilin-   (c)    14-O-[3-(S*)-((N—BOC—(R)-Valyl-amino-cyclohexan-1-(R*)-yl)sulfanyl)-acetyl]mutilin,    and-   (d)    14-O-[3-(R*)-((N—BOC—(R)-Valyl-amino-cyclohexan-1-(S*)-yl)sulfanyl)-acetyl]mutilin    is obtained. ¹H-NMR(d₆-DMSO):-   (a): 6.5(d,1H,NH,J=8.1 Hz), 6.15, 5.1 (2×m,H₁₉,H₂₀,H₂₁),    5.52(d,1H,J=5.2 Hz,H₁₄), 3.4(m, 1H, H₁₁,), 3.55 (m,1H,CHN), 3.7    (m,α-valyl), 3.2 (m,2H,H₂₂), 2.7 (m,1H,SCH), 1.4 (s,9H, tert.butyl),    1.18,1.45(2×s,(CH3)₁₅,(CH3)₁₈), 0.75,0.88 (2×d,(CH₃)₁₆,(CH₃)₁₇,    J=5.4 Hz).-   (b): 6.15, 5.1 (2×m,H₁₉,H₂₀,H₂₁), 5.52(d,1H,J=5.2 Hz,H₁₄),    3.4(m,1H,H₁₁,), 3.55 (m,1H,CHN), 3.70 (m,α-valyl), 3.2 (m,2H,H₂₂),    2.7 (m,1H,SCH), 1.4 (s,9H,tert.butyl), 1.18,1.45(2×s,    (CH3)₁₅,(CH3)₁₈), 0.75,0.88 (2×d,(CH₃)₁₆,(CH₃)₁₇,J=5.4 Hz).-   (c): 6.15, 5.1 (2×m,H₁₉,H₂₀,H₂₁), 5.52(d,1H,J=5.2 Hz,H₁₄),    3.4(m,1H,H₁₁,), 3.9 (m,1H,CHN), 3.75 (m,α-valyl), 3.2 (m,2H,H₂₂),    3.15 (m,1H,SCH), 1.4 (s,9H,tert.butyl), 1.18,1.45(2×s,    (CH3)₁₅,(CH3)₁₈), 0.75,0.88 (2×d,(CH₃)₁₆,(CH₃)₁₇,J=5.4 Hz).-   (d): 6.15, 5.1 (2×m,H₁₉,H₂₀,H₂₁), 5.52(d,1H,J=5.2 Hz,H₁₄),    3.4(m,1H,H₁₁,), 3.9 (m, 1H,CHN), 3.70 (m,α-valyl), 3.2 (m,2H,H₂₂),    3.15 (m,1H,SCH), 1.4 (s,9H,tert.butyl), 1.18,1.45(2×s,    (CH3)₁₅,(CH3)₁₈), 0.75,0.88 (2×d,(CH₃)₁₆,(CH₃)₁₇,J=5.4 Hz).

Example I-G14-O-[3-(R*)-((R)-Valyl-amino-cyclohexan-1-(R*)-yl)-sulfanyl)-acetyl]-mutilinand14-O-[3-(S*)-((R)-Valyl-amino-cyclohexan-1-(S*)-yl)-sulfanyl)-acetyl]-mutilinin the form of a hydrochloride (mixture of trans-diastereoisomers)

620 mg of a 1:1 mixture of14-O-[3-(R*)-((N—BOC—(R)-valyl-amino-cyclohexan-1-(R*)-yl)sulfanyl)-acetyl]mutilinand 14-O-[3-(S*)-((N—BOC—(R)-valyl-amino-cyclohexan-1-(S*)-ylsulfanyl)-acetyl]mutilin are dissolved in a mixture of 10 ml of dryetheric HCl and 10 ml of CH₂Cl₂. The mixture is stirred for 5 hours anda mixture of trans-diastereoisomers of14-O-[3-(R*)-((R)-valyl-amino-cyclohexan-1-(R*)-yl)-sulfanyl)-acetyl]-mutilinof14-O-[3-(S*)-((R)-valyl-amino-cyclohexan-1-(S*)-yl)-sulfanyl)-acetyl]-mutilinin the form of a hydrochloride is obtained and isolated.¹H-NMR(d₆-DMSO,): Rotamer. 8.4 (m,1H,C═ONH), 8.15 (b,3H,NH₃ ⁺), 6.15,5.1 (2×m,H₁₉,H₂₀,H₂₁), 5.52(d,1H,J=5.2 Hz,H₁₄), 3.95 (m1H, CHNH₃⁺,3.4(m,1H,H₁₁,), 3.55 (m,α-valyl), 3.2-3.3 (m,2H,H₂₂), 3.18 (m,1H,SCH),1.18,1.45(2×s,(CH3)₁₅,(CH3)₁₈), 0.9 (m,6H,CH(CH₃)₂), 0.75,0.88(2×d,(CH₃)₁₆,(CH₃)₁₇,J=5.4 Hz)

Example I-H14-O-[3-(R*)-((R)-Valyl-amino-cyclohexan-1-(S*)-yl)-sulfanyl)-acetyl]-mutilinand14-O-[3-(S*)-((R)-Valyl-amino-cyclohexan-1-(R*)-yl)-sulfanyl)-acetyl]-mutilinin the form of a hydrochloride (mixture of cis-diastereoisomers)

is obtained analagosouly to the method of Example I-G, but using a 1:1mixture of14-O-[3-(R*)-((N—BOC—(R)-valyl-amino-cyclohexan-1-(S*)-yl)sulfanyl)-acetyl]mutilinand 14-O-[3-(S*)-((N—BOC—(R)-valyl-amino-cyclohexan-1-(R*)-ylsulfanyl)-acetyl]mutilin as a starting material.

¹H-NMR(d₆-DMSO): Rotamers. 8.52 (m,1H,C═ONH), 8.2 (b,3H,NH₃ ⁺), 6.15,5.1 (2×m,H₁₉, H₂₀,H₂₁), 5.52(d,1H,J=5.2 Hz,H₁₄), 3.58 (m1H, CHNH₃ ⁺,3.4(m,1H,H₁₁,), 3.48 (m,α-valyl), 3.2-3.3 (m,2H,H₂₂), 2.75 (m,1H,SCH),1.18,1.45(2×s,(CH3)₁₅,(CH3)₁₈), 0.9 (m,6H,CH(CH₃)₂), 0.75,0.88(2×d,(CH₃)₁₆,(CH₃)₁₇,J=5.4 Hz)

Example I-I 14-O-[((N—(R)-Valyl-azepan-4-(R/S)-yl)-sulfanylacetyl)]-mutilin In the form of a hydrochloride I-IA)4-(R/S)-(2,4,6-Trimethyl-benzyl-sulfanyl)-azepan-2-one

A solution of 828 mg of3-(R/S)-(2,4,6-trimethyl-benzyl-sulfanyl)-cyclohexanone-oxime and 570 mgof toluenesulfonylchloride in 5 ml of pyridine is stirred at RT for 4hours and additional 2 hours at 60°. The mixture obtained is distributedbetween diluted sulfuric acid (2 ml H₂SO₄ conc. in 15 ml H₂O) andCH₂Cl₂, the organic phase obtained is dried, solvent is evaporated andthe evaporation residue is subjected to chromatography.4-(R/S)-(2,4,6-Trimethyl-benzyl-sulfanyl)-azepan-2-one is obtained.¹H-NMR(d-6-DMSO): 7.5 (m,1H,NHCO), 6.8 (s,2H,arom.H), 3.75(s,2H,C₆H₅CH₂S—),3.2 (m, 1H,CHN), 3.1(m,3H, CH₂NH,CHS)AB-system:v_(A)=2.72,v_(B)=2.65(2H,CH2C═O, J=13.4 Hz, J=4.5 Hz) 2.13 2.15,2.3(9H,3×CH₃)

I-IB) 4-(R/S)-(2,4,6-Trimethyl-benzyl-sulfanyl)-azepane

3.3 g of 4-(R/S)-(2,4,6-trimethyl-benzyl-sulfanyl)-azepan-2-one areadded to a mixture of 15 ml of a 1M-solution of LiAlH₃ and 50 ml THF areadded. The mixture obtained is heated for 1 hour at 80°, poured into 200ml of a 20% aqueous NH₄Cl-solution and the mixture obtained is extractedwith EtAc. The organic phase obtained is dried and solvent isevaporated. 4-(R/S)-(2,4,6-Trimethyl-benzyl-sulfanyl)-azepane isobtained.

I-IC) N—BOC-(4-(R/S)-(2,4,6-Trimethyl-benzyl-sulfanyl))-azepane

A solution of 2.63 g of4-(R/S)-(2,4,6-trimethyl-benzyl-sulfanyl)-azepane, 2.18 g ofBOC-anhydride and 1 g of triethylamine in 100 ml of THF is stirred at25° for 12 hours and from the mixture obtained solvent is evaporated.The evaporation residue obtained is distributed between CH₂Cl₂ and 1MHCl. Solvent from the organic phase obtained is evaporated and theevaporation residue is subjected to chromatography.N—BOC-(4-(R/S)-(2,4,6-trimethyl-benzyl-sulfanyl))-azepane is obtained.¹H-NMR(d₆-DMSO): 6.8 (s,2H,arom.H), 3.75(s,2H,C₆H₅CH₂S—),3.2-3.5(m,4H,CH₂NHCH₂), 2.9(m,1H,CHS), 2.132.15,2.3(9H, 3×CH₃)

I-IC) N—BOC-4-(R/S)-Azepan-thiol

is obtained analogously to the method of Example II-D, but usingappropriate starting materials.

I-ID) 14-O—[((N—BOC-Azepan-4-(R/S)-yl)-sulfanyl acetyl)]-mutilin

A solution of 1.06 g of pleuromutilin-22-O-tosylate dissolved in 10 mlTHF is slowly added to a solution of 420 mg ofN—BOC-(4-(R/S)-azepane-thiol and 220 mg of potassium-tert.butylate in 25ml of THF and the mixture obtained is stirred for 2 hours. The mixtureobtained is distributed between brine and EtAc, the mixture obtained isextracted with 0.1N HCl , the organic phase obtained is dried, solventis evaporated and the evaporation residue obtained is subjected tochromatography. 14-O—[((N—BOC-azepan-4-(R/S)-yl)-sulfanylacetyl)-mutilin is obtained. ¹H-NMR(d₆-DMSO): 6.15, 5.1(2×m,H₁₉,H₂₀,H₂₁), 5.52(d,1H,J=5.2 Hz,H₁₄), 4.52 (d,1H,OH,J=6.2Hz)3.4(t,1H,H₁₁,J=6.2 Hz), 3.1-3.4 (m,6H,H_(22,)CH₂NCH₂), 2.9(m,1H,SCH), 1.4 (s,9H,tert.butyl), 1.18,1.45(2×s,(CH3)₁₅,(CH3)₁₈),0.75,0.88 (2×d,(CH₃)₁₆,(CH₃)₁₇,J=5.4 Hz)

I-IE) 14-O-[((Azepan-4-(R/S)-yl)-sulfanyl acetyl)]-mutilin in the formof a hydrochloride

400 mg of 14-O—[((N—BOC-azepan-4-(R/S)-yl)-sulfanyl-acetyl)-mutilin aredissolved in a mixture of 10 ml of dry etheric HCl and 10 ml of CH₂Cl₂.The mixture obtained is stirred for 5 hours and14-O-[((azepan-4-(R/S)-yl)-sulfanyl acetyl)]-mutilin in the form of ahydrochloride is isolated. Characterisation data see TABLE 1, Example14.

I-IF) 14-O-[((N—(R)-Valyl-azepan-4-(R/S)-yl)-sulfanyl acetyl)]-mutilinin the form of a hydrochloride

A mixture of 245 mg 14-O-[((azepan-4-(R/S)-yl)-sulfanyl acetyl)]-mutilinin the form of a hydrochloride, 110 mg of BOC—R-valin, 95 mg of EDC and100 mg of triethylamine in 10 ml THF is stirred at RT for 2 hours. Themixture obtained is distributed between brine and EtAc, the organicphase obtained is dried, solvent is evaporated and the evaporationresidue obtained is subjected to chromatography.

14-O—[((N—BOC—(R)-Valyl-azepan-4-(R/S)-yl)-sulfanylacetyl)]-mutilin-hydrochloride is obtained. The BOC-protecting group iscleaved by treatment with 5 ml of etheric HCl and14-O—[((N—(R)-Valyl-azepan-4-(R/S)-yl)-sulfanyl acetyl)]-mutilin in theform of a hydrochloride is obtained. Characterisation data see TABLE 1,Example 15.

Example I-J 14-O-[((Azepan-2-one-4-(R/S)-yl)-sulfanyl acetyl)]-mutilin

-   -    is obtained analagously to the method of Example IAB), starting        from 4-(R/S)-mercapto-azepan-2-one. Characterisation data see        TABLE 5, Example 43.

Example I-K14-O-{[(3-Oxo-cyclopentan-(R/S)-yl)-sulfanyl]-acetyl}-mutilin

A solution of 3.95 g of 14-mercapto-acetyl-mutilin in 5 ml of pyridineis treated with 0.81 g of cyclopent-2-enone and a catalytical amount oftriethylamine. The mixture obtained is stirred for 3 hours at roomtemperature, diluted with EtAc and extracted with 1N HCl and H₂O. Theorganic phase obtained is dried, solvent is evaporated and theevaporation residue obtained is subjected to chromatography.14-O-{[(3-oxo-cyclopentan-(R/S)-yl)-sulfanyl]-acetyl}-mutilin isobtained. Characterisation data see in TABLE 5, Example 44.

Example I-L14-O-{[(3-Hydroxyimino-cyclopentan-(R/S)-yl)-sulfanyl]-acetyl}-mutilin(syn and anti forms)

3.88 g of 14-O-{[(3-oxo-cyclopentan-(R/S)-yl)-sulfanyl]-acetyl}-mutilinare stirred overnight with 566 mg of hydroxylamine hydrochloride and1.13 ml of triethylamine in 40 ml of DMF. From the mixture obtainedsolvent is distilled off, the distillation residue obtained is taken upin EtAc and the mixture obtained is extracted with 0.1N HCl and brine.The organic phase obtained is dried and solvent is evaporated. A mixtureof14-O-{[(3-hydroxyimino-cyclo-pentan-(R/S)-yl)-sulfanyl]-acetyl}-mutilinin the syn*- and in the anti*-form is obtained which mixture is eitherseparated by chromatography to obtain the pure syn- and the pureanti-forms, or is used in the form of the mixture obtained in furtherreaction steps. Characterisation data see TABLE 3, Example 24.

Example I-M14-O-{[(3-(2-Diethylamino-ethoxyimino)-cyclopentan-(R/S)-yl)-sulfanyl]-acetyl}-mutilinin the form of a hydrochloride

200 mg of14-O-{[(3-hydroxyimino-cyclopentan-(R/S)-yl)-sulfanyl]-acetyl}-mutilinand 70 mg of diethylaminoethylchloride hydrochloride are stirred in 5 mlof CH₂Cl₂, 90 mg of potassium tert butoxide are added and stirring iscontinued for 2 days at RT. From the mixture obtained solvent isevaporated, the evaporation residue is subjected to chromatography, therelevant chromatographic fractions obtained are distributed between Et₂Oand 0.1N HCl and the aqueous layer is lyophilized.14-O-{[(3-(2-diethylamino-ethoxyimino)-cyclopent-(R/S)-yl)-sulfanyl]-acetyl}-mutilinhydrochloride (syn/anti mixture)is obtained. Characterisation data seeTABLE 3, Example 26.

Example I-N14-O-[(2-(R*)-((R)-Valyl)-amino-cyclohexan-1-(R*)-yl)-sulfanylacetyl)]-mutilin-hydrochloride I-NA)14-O-[((2-(R*)-Aminocyclohexan-1-(R*)-yl)-sulfanyl acetyl)]-mutilin

1.06 g of pleuromutilin-22-O-tosylate dissolved in 5 ml of THF areslowly added to a solution of 334 mg of2-(R*)-aminocyclohexan-(R*)-thiol in the form of a hydrochloride (seee.g. G.Kavadias and R.Droghini, Can.J.Chem. 1978,56, 2743)and 92 mgsodium in 50 ml of EtOH, the mixture obtained is stirred for 2 hours,distributed between brine and EtAc, extracted with 0.1N HCl and dried.From the mixture obtained solvent is evaporated and the evaporationresidue is subjected to chromatography.14-O-[((2-(R*)-aminocyclohexan-1-(R*)-yl)-sulfanyl acetyl)]-mutilin isobtained. ¹H-NMR(d₆-DMSO): 6.15, 5.1 (2×m,H₁₉,H₂₀,H₂₁), 5.52(d,1H,J=5.2Hz,H₁₄), 2.45(m,1H,CHNH), 3.21 (s,2H,H₂₂), 3.4(d,1H, H₁₁,J=5 Hz),2.55(m,1H,CHS), 1.18,1.45 (2×s,(CH3)₁₅,(CH3)₁₈), 0.9 (m,6H,CH(CH₃)₂),0.75,0.88 (2×d,(CH₃)₁₆,(CH₃)₁₇,J=5.4 Hz).

I-NB) 14-O-[(2-(R*)-((R)-Valyl)-amino-cyclohexan-1-(R*)-yl)-sulfanylacetyl)]-mutilin in the form of a hydrochloride

A mixture of 245 mg of14-O-[((2-(R*)-aminocyclohexan-1-(R*)-yl)-sulfanyl acetyl)]-mutilin, 110mg of BOC—(R)-valin, 95 mg of EDC and 68 mg of HOBT in 10 ml of THF isstirred at RT for 2 hours. The mixture obtained is distributed betweenbrine and EtAc, the organic phase obtained is dried, solvent isevaporated and the evaporation residue is subjected to chromatography.14-O-[((2-(R*)-(N—BOC—(R)-Valyl)-amino-cylohexan-1-(R*)-yl)-sulfanylacetyl)]-mutilin is obtained. The BOC-protecting group is cleaved bytreatment with 5 ml of etheric HCl and14-O-[(2-(R*)-((R)-valyl)-amino-cyclohexan-1-(R*)-yl)-sulfanylacetyl)]-mutilin in the form of a hydrochloride is obtained.¹H-NMR(d₆-DMSO): Diastereoisomers):8.45(m, 1H, NHC═O),8.1(b,3H,NH₃ ⁺),6.15, 5;1 (2×m,H₁₉,H₂₀,H₂₁), 5.52(d,1H,J=5.2 Hz,H₁₄), 3.55 (m,1H,a-H-valyl),3.60(m,1H,CHNH), 3.26-3.35 (m,2H,H₂₂),3.4(m,1H, H₁₁), 4.5(d,1H,OH, J=6.2 Hz), 2.6,2.75(2×m,1H,CHS), 1.25 (b,3H,CH₃CS),1.18,1.45(2×s,(CH3)₁₅,(CH3)₁₈), 0.9 (m,6H,CH(CH₃)₂), 0.75,0.88(2×d,(CH₃)₁₆,(CH₃)₁₇,J=5.4 Hz)

Example I-O 44-O-{[(3S,3aS,6S,6aR)-6-Amino-hexahydro-furo[3,2-b]furan-3-ylsulfanyl]-acetyl}-mutilinhydrochloride I-OA) Toluene-4-sulfonic acid(3R,3aS,6R,6aR)-6-hydroxy-hexahydro-furo[3,2-b]furan-3-yl ester

A solution of 5 g of (3R,3aS,6R,6aR)-hexahydro-furo[3,2-b]furan-3,6-diolin 50 ml of pyridine is stirred for 16 h with 7.8 g oftoluenesulfonylchloride. From the mixture obtained solvent is distilledoff and the distillation residue obtained is dissolved in EtAc andextracted with 1N HCl, saturated aqueous NaHCO₃-solution and H₂O. Theorganic layer obtained is dried, solvent is evaporated and theevaporation residue is subjected to chromatography. Toluene-4-sulfonicacid (3R,3aS,6R,6aR)-6-hydroxy-hexahydro-furo[3,2-b]furan-3-yl ester isobtained. ¹HNMR(DMSO-d₆): 7.8 (d,2H,Ar—H,J=8.6 Hz), 7.5 (d,2H,Ar—H,J=8.6Hz), 4.8-4.9 (m,2H,H-3, 6-OH), 4.4 (dd,1H,H-3a,J=4.7 and 5.0 Hz), 4.2(dd,1H,H-6a,J=4.7 and 4.8 Hz), 3.9-4.0 (m,1H,H-6), 3.7-3.8 (m,2H,H-2 andH-5), 3.6 (d,1H,H-2,J=9.3 and 7.1 Hz),3.2-3.4(m,1H,H-5), 2.4 (s, 3H,Ar—CH₃).

I-OB) (3R,3aR, 6S,6aR)-6-Azido-hexahydro-furo[3.2-b]furan-3-ol

A solution of 2.5 g of toluene-4-sulfonic acid(3R,3aS,6R,6aR)-6-hydroxy-hexahydro-furo[3,2-b]furan-3-yl ester in 30 mlof DMF is heated with 0.8 g of sodium azide under reflux for 2 hours,solvent is distilled off and the distillation residue obtained isdissolved in EtAc and extracted with H₂O. The organic phase obtained isdried and solvent is evaporated. (3R,3aR,6S,6aR)-6-azido-hexahydro-furo[3,2-b]furan-3-ol is obtained.

I-OC){(3S,3aR,6R,6aR)-6-Hydroxy-hexahydro-furo[3.2-b]furan-3-yl}-carbamicacid tert-butyl ester

To a solution of 1.5 g of(3R,3aR,6S,6aR)-6-azido-hexahydro-furo[3,2-b]furan-3-ol in 25 ml ofdioxane 75 mg of palladium on charcoal (10%) are added and the mixtureobtained is subjected to hydrogenation. The mixture obtained is filteredand stirred overnight with 3.2 ml of ethyidiisopropylamine and 4.1 g of(BOC)₂O. From the mixture obtained solvent is evaporated. Theevaporation residue obtained is dissolved in EtAc and extracted withsaturated aqueous sodium NaHCO₃-solution, 1N HCl and brine. The organicphase obtained is dried, solvent is evaporated and the evaporationresidue obtained is subjected to chromatography.{(3S,3aR,6R,6aR)-6-hydroxy-hexahydro-furo[3,2-b]furan-3-yl}-carbamicacid tert-butyl ester is obtained. ¹HNMR(DMSO-d₆): 7.1 (bs,1H,NH), 4.8(d,1H,6-OH,J=10 Hz), 4.3 (dd,1H,H-6a,J=4.6 and 4.3 Hz), 4.27(d,1H,H-3a,J=4.3 Hz), 4.0-4.1 (m,1H,H-6), 3.2-3.85 (m,5H,2×H-2, H-3,2×H-5), 1.4 (s,9H,tert.butyl).

I-OD) Toluene-4-sulfonic acid(3R,3aS,6S,6aR)-6-tert-butoxycarbonylamino-hexahydro-furo[3,2-b]furan-3-ylester

A solution of 700 mg of{(3S,3aR,6R,6aR)-6-hydroxy-hexahydro-furo[3,2-b]furan-3-yl}-carbamicacid tert-butyl ester in 10 ml of pyridine is stirred for 16 hours with785 mg of toluolsulfonylchloride, solvent is distilled off and thedistillation residue is dissolved in EtAc and extracted with 1N HCl,saturated aqueous NaHCO₃-solution and H₂O. The organic layer obtained isdried and solvent is evaporated. Toluene-4-sulfonic acid(3R,3aS,6S,6aR)-6-tert-butoxycarbonylamino-hexahydro-furo[3,2-b]furan-3-ylester is obtained.

I-OE)14-O-{[(3S,3aS,6S,6aR)-6-tert-Butoxycarbonylamino-hexahydro-furo[3.2-b]furan-3-ylsulfanyl]-acetyl}-mutilin

267 mg of potassium tert.butoxide are added to a solution of 950 mg oftoluene-4-sulfonic acid(3R,3aS,6S,6aR)-6-tert-butoxycarbonylamino-hexahydro-furo[3,2-b]furan-3-ylester and 1032 mg of 14-mercapto-acetyl-mutilin in 20 ml of DMSO. Themixture obtained is stirred at 70° for 1 hour and distributed betweenEtAc and brine. The organic phase obtained is washed with H₂O, dried andsolvent is evaporated. The evaporation residue obtained is subjected tochromatography.14-O-{[(3S,3aS,6S,6aR)-6-tert-butoxycarbonyl-amino-hexahydro-furo[3,2-b]furan-3-ylsulfanyl]-acetyl}-mutilinis obtained. ¹HNMR(DMSO-d₆): 7.1 (bs,1H,NH), 6.1, 5.05, 5.0(3×m,H₁₉,H₂₀,H₂₁), 5.55 (d,1H,H₁₄, J=8.2 Hz), 4.5 (m,2H,H₁₁—OH,H-3a′),4.4 (d, 1H, H-6a′, J=4 Hz), 3.3-4.0 (m,9H,H-2′,H-3′,H-5′,H-6′,H₁₁,H₂₂),1.36 (s,9H,tert-butyl), 1.34, 1.05 (2×s, (CH₃)₁₅, (CH₃)₁₈), 0.8, 0.62(2×d (CH₃)₁₆, (CH₃)₁₇,J=6.8 Hz).

I-OF)14-O-{[(3S,3aS,46S,6aR)-6-Amino-hexahydro-furo[3,2-b]furan-3-ylsulfanyl]-acetyl}-mutilin

950 mg of14-O-{[(3S,3aS,6S,6aR)-6-tert-butoxycarbonylamino-hexahydro-furo[3,2-b]furan-3-ylsulfanyl]-acetyl}-mutilinare dissolved in 20 ml of CH₂Cl₂ and the mixture obtained is stirred for2 hours with 3 ml of TFA. The mixture obtained is diluted with EtAc andextracted with saturated aqueous NaHCO₃-solution. The organic phaseobtained is dried and solvent is evaporated.14-O-{[(3S,3aS,6S,6aR)-6-amino-hexahydro-furo[3,2-b]furan-3-ylsulfanyl]-acetyl}-mutilinis obtained.

I-OG)14-O-{[(3S,3aS,6S,6aR)-6-Amino-hexahydro-furo3,2-b]furan-3-ylsulfany]-acetyl}-mutilinin the form of a hydrochloride

180 mg of14-O-{[(3S,3aS,6S,6aR)-6-amino-hexahydro-furo[3,2-b]furan-3-ylsulfanyl]-acetyl}-mutilinare distributed between diethylether and 0.1N HCl. The aqueous layerobtained is lyophilized.14-O-{[(3S,3aS,6S,6aR)-6-Amino-hexahydro-furo[3,2-b]furan-3-ylsulfanyl]-acetyl}-mutilinin the form of a hydrochloride is obtained. Characterisation data see inTABLE 4, Example 36a above.

Example I-P14-O-{[(3S,3aS,6S,6aR)-6-((R)-Amino-3-methyl-butyrylamino)-hexahydro-furo[3,2-b]furan-3-ylsulfanyl]-acetyl}-mutilinin the form of a hydrochloride

A solution of 400 mg of14-O-{[(3S,3aS,6S,6aR)-6-amino-hexahydro-furo[3,2-b]furan-3-ylsulfanyl]-acetyl}-mutilinin 20 ml of CH₂Cl₂ is treated with 128 mg of N—Boc-(R)-valine, 147 mg ofEDC, 104 mg of HOBT and the mixture obtained is stirred overnight at RT.The mixture obtained is diluted with CH₂Cl₂, extracted with H₂O, driedand solvent is evaporated. The evaporation residue obtained is subjectedto chromatography on silica gel, relevant chromatographic fractionsobtained are treated again with TFA in CH₂Cl₂, solvent is evaporated,the evaporation residue obtained is distributed between Et₂O and 0.1NHCl and the aqueous layer obtained is lyophilized.14-O-{[(3S,3aS,6S,6aR)-6-((R)-2-amino-3-methyl-butyrylamino)-hexahydro-furo[3,2-b]furan-3-ylsulfanyl]-acetyl}-mutilinin the form of a hydrochloride is obtained. Characterisation data see inTABLE 5, Example 38a.

Example I-Q 14-O-[((3-(R/S)-Amino-cyclohexan-1-(R/S)-yl)-sulfanylacetyl)]-mutilin in the form of a hydrochloride

10.6 g of pleuromutilin-22-O-tosylate dissolved in 10 ml of THF areslowly added to a solution of 5.2 g ofN—BOC-3-(R/S)-mercapto-cyclohexylamin and 2.74 g ofpotassium-tert.butylate in 250 ml of THF. The mixture obtained isstirred for 2 hours, distributed between brine and EtAc, and extractedwith 0.1N HCl. The organic phase obtained is dried, solvent isevaporated and the evaporation residue obtained is subjected ochromatography.14-O-[((N—BOC-3(R/S)-amino-cyclohexan-1-(R/S)-yl)-sulfanylacetyl)]-mutilin is obtained and is converted into14-O-[((3-(R/S)-Amino-cyclohexan-1-(R/S)-yl)-sulfanyl acetyl)]-mutilinin the form of a hydrochloride by treatment with etheric HCl.

¹H-NMR(d₆-DMSO): 8.0 (b,3H,NH₃ ⁺), 6.15, 5.1 (2×m,H₁₉,H₂₀,H₂₁),5.52(d,1H,J=5.2 Hz,H₁₄), 3.4(m,1H,H₁₁,), 3.3 (m,2H,H₂₂), 2.9 (m,1H,NCH),2.7(m,1H,CHS), 1.18,1.45 (2×s,(CH3)₁₅, (CH3)₁₈), 0.75,0.88(2×d,(CH₃)₁₆,(CH₃)₁₇,J=5.4 Hz)

II. Preparation of Intermediates (Starting Materials) for thePreparation of a (SPECIAL) Pleuromutilin of the Present InventionExample II-A 14-Mercapto-acetyl-mutilin II-M)14-O-[(Carbamimidoylsulfanyl)acetyl]mutilin-tosylate

A solution of 15.2 g of thiourea and 106.4 g ofpleuromutilin-22-O-tosylate in 250 ml of acetone is heated under refluxfor 1.5 hours, solvent is removed and 100 ml of hexane are added. Aprecipitate forms, is filtrated off and dried.

14-O-[(carbamimidoylsulfanyl)acetyl]mutilin-tosylate is obtained.

II-AB) 14-Mercapto-acetyl-mutilin

A solution of 4.7 g of Na₂S₂O₅ in 25 ml of H₂O is added to a solution of12.2 g of 14-O-[(carbamimidoylsulfanyl)acetyl]mutilin-tosylate in amixture of 20 ml of EtOH and 35 ml of H₂O (warmed to ca. 90°). 100 ml ofCCl₄ are added to the reaction mixture obtained and the mixture obtainedis heated under reflux for ca. 2 hours. The two-phase system obtained isseparated, the organic phase is dried and solvent is evaporated.14-mercapto-acetyl-mutilin is obtained.

Example II-B N—BOC-3(R)-methylsulfonyloxy-piperidine II-BA)N—BOC-3(R)-Hydroxy-piperidine

A suspension of 3.48 g of 3-(R)-hydroxypiperidine, 8.72 g ofdi-tert.butyl-dicarbonat and 4 g of N-metyl-morpholine in 70 ml ofdioxane is stirred for 18 hours at RT. From the mixture obtained solventis evaporated and the evaporation residue obtained is dissolved inCH₂Cl₂ and extracted with 1N HCl. The organic phase obtained is driedand solvent is evaporated. N—BOC-3(R)-hydroxy-piperidine is obtained.

II-BB) N—BOC-3(R)-methylsulfonyloxy-piperidine

A solution of 5.08 g of N—BOC-3(R)-hydroxy-piperidine and 8.7 g ofmethanesulfonic acid anhydride in 100 ml pyridine is stirred at RT for22 hours, pyridine is distilled off, the distillation residue isdissolved in CH₂Cl₂, the mixture obtained is extracted with 1N HCl, theorganic phase obtained is dried, solvent is evaporated and theevaporation residue obtained is subjected to chromatography.N—BOC-3(R)-methylsulfonyloxy-piperidine is obtained.

¹H-NMR(CDCl₃): 4.7(m,1H,CHOSO₂CH₃), 3.2-3.6(m,4H,CHN),3.0(s,3H,CH₃SO₂),1.4(m, 9H,tert.butyl).

Example II-C N—BOC-Piperidine-3(S)-thiol II-CA)N—BOC-3-(S)-Thioacetoxy-piperidine

A solution of 2.2 g of N—BOC-3-(R)-hydroxy-piperidine in 10 ml of THF isadded under argon and 1 ml of thiolacetic acid to a solution of 3.4 g oftriphenylphosphine and 2.65 ml of azadicarbonic acid-isopropylate in 10ml of THF. The mixture obtained is kept for 18 hours at 70°, solvent isevaporated and the evaporation residue obtained is subjected tochromatography. N—BOC-3-(S)-thioacetoxy-piperidine is obtained. ¹H-NMR(CDCl₃): 3.78 (dd,1H,NCH₂CHS, J=3.1 Hz, J=13.3 Hz), 3.5-3.6 (m,2H,CHSC═O, NCH₂CH₂), 2.32(s,3H,SC═OCH₃),1.46(s,9H, tert.butyl)

II-CB) N—BOC-Piperidine-3(S)-thiol

To a solution of 259 mg of N—BOC-3-(S)-thioacetoxy-piperidine in 10 mlof MeOH a solution of 262 mg of NaSCH₃ in 5 ml of MeOH is added and themixture obtained is stirred for 2 hours, solvent is evaporated and theevaporation residue obtained is distributed between EtAc and aqueousHCl. Solvent from the organic phase obtained is evaporated.N—BOC-piperidine-3(S)-thiol is obtained. ¹H-NMR(d₆-DMSO): 2.6 (d,1H,SH,J=7.2 Hz), 2.9-2.7 (m,3H, NCH₂,CHS), 1.35 (b,9H,tert.butyl). MS(ESI)457(2M+Na).

Example II-D 3-(N—BOC—(R)-Valyl-amino)-cyclohexane-(R/S)-thiol II-DA)3-(R/S)-(2,4,6-Trimethyl-benzyl-sulfanyl)-cyclohexanone

A solution of 3.32 g of 2,4,6-trimethyl-benzylmercaptane and 3.84 g ofcyclohexen-3-one in 30 ml of pyridine is heated at 40° for 3 hours. Themixture obtained is poured into 200 ml of 1M HCl and the mixtureobtained is extracted with CH₂Cl₂. The organic phase obtained is dried,solvent is evaporated and the evaporation residue is subjected tochromatography on silica gel.3-(R/S)-(2,4,6-trimethyl-benzyl-sulfanyl)-cyclohexanone is obtained.

¹H-NMR(d₆-DMSO): 6.8 (s,2H,arom.H), 3.8 (s,2H,C₆H₅CH₂S—), 3.3(m,1H,CHS), 3.18 (dd,1H, CHC═NOH, J=4 Hz, 13.9 Hz), 2.65-2.8,2.44-2.49(2×m,4H,CH₂C═OCH₂),2.15,2.3(9H,3×CH₃).

II-DB) 3-(R/S)-(2,4,6-Trimethyl-benzyl-sulfanyl)-cyclohexanone-oxime(syn and anti-forms)

A solution of 5.24 g of3-(R/S)-(2,4,6-trimethyl-benzyl-sulfanyl)-cyclohexanone, 1.38 g ofhydroxylamine in the form of a hydrochloride and 2 g of triethylamine in50 ml of MeOH is stirred at 25° for 12 hours, the mixture obtained ispoured into 200 ml of brine and the mixture obtained is extracted withCH₂Cl₂. The organic phase obtained is dried and solvent is evaporated. Amixture of the syn- and anti forms of3-(R/S)-(2,4,6-trimethyl-benzyl-sulfanyl)-cyclohexanone-oxime isobtained which is subjected to chromatography. Pure syn- and pureanti-3-(R/S)-(2,4,6-trimethyl-benzyl-sulfanyl)-cyclohexanone-oxime isobtained.

¹H-NMR(d₆-DMSO) of the syn-form: 10.3 (s,1H,OH), 6.8 (s,2H,arom.H), 3.75(s,2H, C₆H₅CH₂S—), 2.88 (m,1H,CHS), 3.18 (dd,1H,CHC═NOH, J=4 Hz,13.9Hz), 2.13 (dd,1H, CHC═NOH, J=5.2 Hz,13.9 Hz), 2.15,2.3(9H, 3×CH₃).

¹H-NMR(d₆-DMSO) of the anti-form: 10.3 (s,1H,OH), 6.8 (s,2H,arom.H),3.75 (s,2H, C₆H₅CH₂S—), 2.92(m,1H,CHS), 2.58 (dd,1H,CHC═NOH, J=4 Hz,13.9Hz), 2.15 (dd,1H, CHC═NOH, J=4.2 Hz,13.6 Hz), 2.15,2.3(9H, 3×CH₃).

II-DC) 3-(R/S)-(2,4,6-trimethyl-benzyl-sulfanyl)-cyclohexyl-(R/S)-amine

2.7 g of 3-(R/S)-(2,4,6-Trimethyl-benzyl-sulfanyl)-cyclohexanone-oximeare added to a mixture of 20 ml of a 1M-solution of LiAlH₃ and 15 ml ofdioxane, the mixture obtained is heated for 1 hour at 80° and themixture obtained is poured into 200 ml of a 20% aqueous NH₄Cl-solution.The mixture obtained is extracted with EtAc, the organic phase obtainedis dried and solvent is evaporated.3-(R/S)-(2,4,6-trimethyl-benzyl-sulfanyl)-cyclohexyl-(R/S)-amine isobtained.

II-DC)3-(N—BOC—(R)-Valyl-amino)-cyclohexan-1-(R/S)-yl-sulfanylmethyl-(2,4,6-trimethyl-benzol)

A mixture of 1.05 g of3-(R/S)-(2,4,6-trimethyl-benzyl-sulfanyl)-cyclohexyl-(R/S)-amine, 870 mgof BOC—R-valine, 760 mg of EDC and 404 mg of triethylamine in 20 ml THFis stirred at RT for 2 hours. The mixture obtained is distributedbetween brine and EtAc, the organic phase obtained is dried, solvent isevaporated and the evaporation residue is subjected to chromatography.3-(N—BOC—(R)-valyl-amino)-cyclohexan-1-(R/S)-yl-sulfanylmethyl-(2,4,6-trimethyl-benzol)is obtained. ¹H-NMR(d₆-DMSO): Rotamers, 7.78, 7.3, 6.52 (3×d,2H,NH),J=7.9 Hz), 6.8, 6.82 (2×s,2H, arom.H), 6.55 (m,1H,NHC═O),3.7(m,1H,a-H-valyl), 3.6 (m,1H,NHCH), 2.75, 3.0 (2×m,1H, CHS),1.39(s,9H,tert.butyl)

II-DD) 3-(N—BOC—(R)-Valyl-amino)-cyclohexane-(R/S)-thiol

10 ml ammonia are condensed at −70° within a solution of 600 mg of3-(N—BOC—(R)-valyl-amino)-cyclohexan-1-(R/S)-yl-sulfanylmethyl-2,4,6-trimethyl-benzolin 15 ml of THF and sodium is added in portions until the solutionremains deep blue. Solid NH₄Cl is added to the mixture obtained and themixture obtained is allowed to warm up to RT, is flushed with nitrogen,the solid residue obtained is filtered off, the filtrate obtained isconcentrated and subjected to chromatography on silica gel.3-(N—BOC—(R)-Valyl-amino)-cyclohexane-(R/S)-thiol is obtained.¹H-NMR(d₆-DMSO): Rotamer, 7.75 (m,1H,NHCHC═O), 6.55 (m,1H,NHC═O),2.75(m,1H,CHS), 2.58(d,1H,SH,J=6.6 Hz), 1.39(s,9H,tert.butyl)

Analogously to the method as set out in Example II-D but usingappropriate starting materials the following compounds are obtained:

Example II-D-1 N—BOC-3-(R/S)-mercapto-cyclohexylamin Example II-D-24-(R/S)-Mercapto-azepan-2-one

4-(R/S)-(2,4,6-trimethyl-benzyl-sulfanyl)-azepan-2-one. ¹H-NMR(d₆-DMSO):6.15, 5.1 (2×m,H₁₉,H₂₀,H₂₁), 5.52(d,1H,J=5.2 Hz,H₁₄), 3.4(m,1H,H₁₁,),3.3 (m,2H,H₂₂), 2.99-3.12(b,2H,CH₂N), 3.18(m,1H,SCH), 2.7 (m,1H,C═OCH),2.67(d,1H,SH,J=5.5 Hz), 2.58(d,1H,C═OCH,J=13.5 Hz), 1.18,1.45(2×s,(CH3)₁₅,(CH3)18), 0.75,0.88 (2×d,(CH₃)₁₆,(CH₃)₁₇,J=5.4 Hz).

Example II-EN—BOC-3-(R/S)-(2,4,6-trimethyl-benzyl-sulfanyl)-cyclohexyl-(R/S)-amine

A solution of 11 g of3-(R/S)-(2,4,6-trimethyl-benzyl-sulfanyl)-cyclohexylamine, 9.15 g ofBOC-anhydride and 4.2 g of triehylamine in 100 ml of THF is stirred at25° for 12 hours, solvent is evaporated and the concentrated residue isdistributed between CH₂Cl₂ and 1M HCl. From the organic phase obtainedsolvent is evaporated and the evaporation residue is subjected tochromatography.N—BOC-3-(R/S)-(2,4,6-trimethyl-benzyl-sulfanyl)-cyclohexyl-(R/S)-amineis obtained. ¹H-NMR(d₆-DMSO): 6.81,(s,1H,NHCO), 6.8 (s,2H, arom.H), 3.75(s,2H,C₆H₅CH₂S—),3.2 (m,1H,CHN), 2.70 (m,1H,CHS), 2.13 2.15,2.3(9H,3×CH₃),1.4(s,9H,tert.butyl)

Example II-F Toluene-4-sulfonic acid(3S,3aS,6R,6aR)-6-hydroxy-hexahydro-furo[3,2-b]furan-3-yl ester andToluene-4-sulfonic acid(3R,3aS,6S,6aR)-6-hydroxy-hexahydro-furan[3,2-b]furan-3-yl ester

A solution of 8.76 g of(3S,3aS,6R,6aR)-hexahydro-furo[3,2-b]furan-3,6-diol in 80 ml of pyridineis stirred for 16 hours with 13.7 g of toluenesulfonylchloride, solventis distilled off and the distillation residue is dissolved in EtAc andextracted with 1N HCl, saturated aqueous NaHCO₃-solution and H₂O. Theorganic layer obtained is dried, solvent is evaporated and theevaporation residue is subjected to chromatography. Toluene-4-sulfonicacid (3S,3aS,6R,6aR)-6-hydroxy-hexahydro-furo[3,2-b]furan-3-yl ester (a)and toluene-4-sulfonic acid(3R,3aS,6S,6aR)-6-hydroxy-hexahydro-furo[3,2-b]furan-3-yl ester (b) areobtained. ¹HNMR(DMSO-d₆) of form (a): 7.8 (d,2H,Ar—H,J=8.2 Hz), 7.5(d,2H,Ar—H,J=8.6 Hz), 4.95 (d,1H,6-OH), 4.8 (m, 1H, H-3), 4.42(dd,1H,H-6a,J=4.6 and 4.8 Hz), 4.38 (d,1H,H-3a,J=4.6), 4.08 (m,1H,H-6),3.8 (m,2H,2×H-2), 3.7, 3.25 (2×dd, 2H, 2×H-5), 2.4 (s, 3H, Ar—CH₃).¹HNMR(DMSO-d₆) of form (b): 7.8 (d,2H,Ar—H,J=8.6 Hz), 7.5(d,2H,Ar—H,J=8.6 Hz), 5.15 (d, 6-OH, J=3.5), 4.9 (m, 1H, H-3), 4.45(dd,1H,H-3a,J=4.3 and 4.8 Hz), 4.2 (d,1H,H6a,J=4.3), 4.0 (m,1H,H-6), 3.7(m,3H,H-2 and 2×H-5), 3.5 (dd,1H,H-2,J=9.5 and 6.3 Hz), 2.4 (s, 3H,Ar—CH₃).

Example II-G N—BOC-4-Hydroxy-piperidin-3-thiol,N—BOC-3-Hydroxy-piperidin-4-thiol

A solution of 1 g of N—BOC-3,4-epoxy-piperidin, 1.9 g oftriphenylsilylmercaptane and 0.7 ml of triethylamine in 12.5 ml of THFis stirred for 24 hours at 70°, and 1.7 g of TBAF and 0.9 ml acetic acidare added. The mixture obtained is stirred for 1 hour and distributedbetween brine and EtAc. The organic phase is dried, solvent isevaporated and the evaporation residue obtained is subjected tochromatography on silica gel. (a): N—BOC-4-Hydroxy-piperidin-3-thiol,and (b): N—BOC-3-hydroxy-piperidin-4-thiol are obtained.

¹H-NMR (CDCl₃) of (a): 4.45, 4.12, 2.8 (3×m,3H,CH₂NCH), 3.31 (dt, 1H,CHO, J=4.3 Hz,J=10 Hz), 2.65,2.6(2×m,2H,CHN,CHS), 1.5(s,9H,tert.butyl).

¹H-NMR (CDCl₃) of (b): 4.25, 3.45 2.7, (3×m,3H,CH₂NCH), 3.2 (m,1H,CHO),2.55(m,2H, NCH,CHS), 1.5(s,9H,tert.butyl).

Test Example In vitro Test Results of Pleuromutilins, Metronidazole andTetracycline

Activity of TEST COMPOUNDS (TCs) against H.pylori strains ATCC 43504,43526, 43629, 49503 and 51652 is determined according to the AgarDilution Method, using Mueller Hinton agar, supplementet with >2 weekold horse blood (5% v/v), incubation at 35° C. for 3 days in a gassystem-generated microaerobic atmosphere according to NCCLSrecommendations, such as disclosed in “Methods for dilutionantimicrobial susceptibility tests for bacteria that grow aerobically“—Fourth edition; approved standard. M7-A4 Vol. 17 No. 2 (1997) andM100-S9 Vol. 19 No. 1(1999).

In vitro activity of the following TEST COMPOUNDS (TC) and ofmetronidazole and tetracycline Is determined:

-   TC-I: a compound of formula I-Valnemulin (Econor®)-   TC-II: a compound of formula of formula I_(s1)-WO0109095-   TC-III: a compound of formula of formula I_(s2)-WO0109095

Results of minimum inhibitory concentrations (MIC in μg/ml)) of TC-I,TC-II and TC-III and of metronidazole (MET) and tetracycline (TEC) invitro tests against Helicobacter pylori (H.pylori) strains as set out inTABLE TEST are as set out in TABLE TEST below:

TABLE TEST Bacterial Strain/ MIC (μg/ml) ATCC number TC-I TC-II TC-IIIMET TEC H.pylori/43504 0.025 <0.0125 0.025 128 0.4 H.pylori/43526 0.050.05 0.05 4 0.4 H.pylori/43629 <0.0125 <0.0125 <0.0125 128 0.4H.pylori/49503 <0.0125 0.025 0.025 4 0.2 H.pylori/51652 0.025 0.0250.025 2 0.2

1. A method influencing the activity of Helicobacter pylori, comprisingtreating Helicobacter pylori with an effective amount of apleuromutilin.
 2. The method according to claim 1, wherein thepleuromutilin is selected from the group consisting of a pleuromutilinof formula

a pleuromutilin of formula

and a pleuromutilin of formula


3. The method according to claim 1, wherein the activity of Helicobacterpylori is decreased.